Bladder Management

Wolfe DL, Legassic M, McIntyre A, Cheung K, Goettl T, Walia S, Loh E, Welk B, Ethans K, Hill D, Hsieh JTC, Mehta S, Teasell RW. (2012). Bladder Health and Function Following Spinal Cord Injury. In Eng JJ, Teasell RW, Miller WC, Wolfe DL, Townson AF, Hsieh JTC, Connolly SJ, Mehta S, Sakakibara BM, editors. Spinal Cord Injury Rehabilitation Evidence. Version 4.0. Vancouver: p. 1-143.


Introduction

Bladder dysfunction in persons with spinal cord injury (SCI) can be disabling medically, physically, and socially. Most people with SCI have some degree of bladder dysfunction.

Normally, the bladder is able to store urine with detrusor (bladder wall muscle) relaxation, at low pressures, until it is socially appropriate to void. At the appropriate time, volitional sphincter muscles relaxation, detrusor contraction, and bladder emptying is achieved in a low pressure, coordinated manner. This coordinated function is achieved by the pons micturition centre and timing is controlled by the frontal cortex. The ability to fill the bladder under low pressure is of utmost importance in maintaining health of the kidneys and maintaining continence. The ability to empty the bladder completely on a regular basis in a low pressure manner is also important in maintaining kidney health and preventing urinary tract infections.

After SCI, neural connectivity to the pons and cortex are disrupted, hence the loss of coordinated bladder filling and emptying. The main goals of bladder dysfunction management following SCI are as follows: achieving regular bladder emptying and avoiding stasis; avoiding high filling and voiding pressures; maintaining continence and avoiding frequency and urgency; and preventing and treating complications such as urinary tract infections (UTIs), stones, strictures and autonomic dysreflexia.

In the present chapter, the literature has been classified into sections pertaining to type of bladder dysfunction i.e., neurogenic overactivity (hypperreflexia) or areflexia, and then methods of treating these either pharmacologically or non-pharmacologically. This includes a section describing literature addressing various bladder management methods. Prevention of complications is best achieved with proper management of the bladder dysfunction type. The last section focuses on UTI prevention and treatment.

Types of Bladder Dysfunction in SCI

 

There are two main types of bladder dysfunction in SCI: 1) neurogenic detrusor overactivity, usually associated with sphincter dysynergia (Detrusor external spincter dyssynergia: DESD) and 2) detrusor areflexia. Occasionally detrusor overactivity secondary to SCI is seen without associated sphincter dysynergia which can result in difficulty with continence. Methods to improve continence in those with or without DESD are often similar and as such, are addressed in the sections on enhancing bladder volumes in DESD.

Detrusor Overactivity Associated with Sphincter Dysynergia (DESD)

This type of dysfunction tends to be seen in those with injuries of the spinal cord affecting the upper motor neurons. In these cases, the lack of coordination of the sphincter and the detrusor is caused by lack of coordination from the pontine micuturition centre due to the spinal cord injury. Both the detrusor and the sphincter are overactive due to lack of control and descending inhibition from the pons and cortex, and both sphincter and detrusor contract reflexively when stretched. The detrusor becomes overactive, reflexively contracting at small volumes against an overactive sphincter, resulting in high bladder pressures. This leads to incontinence (when the detrusor contracts hard enough to overcome the sphincter contraction), incomplete emptying (due to sphincter co-contraction), and reflux (due to high bladder pressures) with resultant recurrent bladder infections, stones, hydronephrosis, pyelonephritis, and renal failure.

Detrusor Areflexia

In the case of a flaccid bladder, loss of detrusor muscle tone prevents bladder emptying and leads to bladder wall damage from over-filling, urine reflux and an increase in infection risk due to stasis. The sphincter tone also tends to be flaccid (at least the external sphincter) causing incontinence, especially with maneuvers that increase intraabdominal pressure (so-called “Valsalva” maneuvers) including straining during transfers, coughing and sneezing. Internal sphincter tone may be intact due to the higher origin of sympathetic innervation, thus complete emptying, even with externally applied suprapubic pressure, may be difficult.

Compared to DESD, patients with detrusor areflexia comprise a much smaller proportion of the SCI population and there is very little literature examining the effectiveness of interventions for this patient subpopulation (patients with detrusor areflexia). Therefore, in the present review the focus is on the literature addressing DESD therapy. In some cases, individual papers may include persons with detrusor areflexia and individual treatments or management methods may still be appropriate for, and applied to those with an areflexic bladder.

DESD Therapy in SCI

Due to the small capacity bladder seen with neurogenic detrusor overactivity, the potential for high bladder pressures leading to reflux, hydronephrosis, and kidney damage, and also due to the potential for incontinence, the goals of therapy are twofold: 1) to enhance bladder volume while lowering bladder filling pressures, and 2) to empty the bladder regularly in a low pressure manner, usually with intermittent catheterization in people with an intact external sphincter, or external drainage in people that have had a procedure to physically or chemically obliterate the external sphincter. Methods to enhance bladder volumes will be discussed first. Note that this pertains to people usually on concomitant intermittent catheterization for drainage. Occasionally the volume enhancing treatments below will be used in combination with an indwelling catheter to avoid leakage around the catheter.

Enhancing Bladder Volumes Pharmacologically

Anticholinergic Therapy for SCI-Related Detrusor Overactivity

The body of the detrusor is comprised of smooth muscle that contains muscarinic receptors triggered by acetylcholine to cause muscle contraction. Therefore, to relax the detrusor and allow it to fill with higher volumes under lower pressure, anticholinergics may be used. Common marketed medications in this class for overactive bladder include oxybutynin (available as Ditropan, Ditropal XL, Oxytrol, Uromax, etc), tolterodine (available as Detrol, Detrol LA), fesoterodine (marketed as Toviaz), and more recently, trospium chloride (Trosec), propiverine hydrochloride (Mictonorm) and M3-receptor specific medications darifenacin (Enablex) and solifenacin (Vesicare). 

Table: Summary Table of Oral Anticholinergics

Discussion

Although there are numerous anticholinergics available for use in overactive bladder, few have actually been used in clinical trials for people with SCI and neurogenic detrusor overactivity. Only those that have been used for SCI-related neurogenic bladder are presented here.

Propiverine has both anticholinergic and calcium channel blocking properties, thus decreasing involuntary smooth muscle contractions. In the SCI population, a double-blind, placebo-controlled, randomized, multicentre (n=124 with 113 completers) study, utilizing 15mg tid administration of propiverine over 2 weeks yielded significant improvement of SCI detrusor hyperreflexia represented by increased maximal cystometric bladder capacity (Stohrer et al. 1999). A subsequent increase in residual urine volume was found, as is the goal in those on concurrent intermittent catheterization. Side effects (primarily dry mouth) were considered tolerable. 

Oxybutynin is an anticholinergic agent used extensively and clinically to treat overactive bladder, yet few studies have been performed on the neurogenic bladder population with this medication. Newer versions of oxybutynin in longer acting forms have sparked renewed research interest in this medication with the hopes of reducing side effects observed with the short acting oxybutynin. O’Leary et al. (2003), in a small (n=10) pre-post trial showed that controlled-release oxybutynin was efficacious for SCI individuals with detrusor hyperreflexia as reflected by significantly increased bladder volume with decreased mean number of voids per 24 hours. However, post-void residual volumes, nocturia and weekly incontinence episodes did not change significantly.

Although oxybutynin is commonly chosen to treat overactive bladder, it is accompanied by bothersome side effects such as dry mouth. A newer anticholinergic that causes less dry mouth, tolterodine, has also been shown to be efficacious for the treatment of neurogenic bladder dysfunction. In a RCT, tolterodine was shown to be significantly better at increasing intermittent catheterization (IC) volumes (p<0.0005) and reducing incontinence (p<0.001) but was similar in its effects on cystometric bladder capacity when compared to placebo (Ethans et al. 2004). This trial was small, thus at risk for type 2 error. As part of the eligibility criteria for this study, subjects were using oxybutynin and intermittent catheterization prior to a 4-day washout in advance of randomization to the tolterodine vs placebo study. This design allowed for a comparison between oxybutynin and tolterodine where the difference in effectiveness of the two drugs were found to be equivocal with respect to IC volumes, degree of incontinence and bladder capacity. Horstmann (2006) found that compared to baseline tolterodine improved reflex volumes, cystometric capacity, and maximum detrusor pressures. Although this study also evaluated trospium, the two medications were only evaluated in a pre-post manner rather than head to head comparison.

Although available in Europe for many years, trospium chloride (an anticholinergic medication that is reported not to cross the blood-brain barrier) has been approved in North America only recently for use in overactive bladder. The efficacy of trospium chloride (20mg bid) in SCI with detrusor hyperreflexia was confirmed by Stohrer et al. (1991) in a RCT. Highly significant (p<0.001) responses were found in favour of trospium chloride vs placebo for increased bladder capacity and compliance, and decreased bladder pressure with low side effects and no effect on flow rate and residual urine volumes. Horstmann et al. (2006) found that trospium chloride improved reflex volumes, cystometric capacity, and maximum detrusor pressures. Presumably the cognitive changes seen on psychometric testing with medications such as oxybutinin are not seen with this medication as it does not cross the blood brain barrier, but this has not been examined specifically in persons with SCI.

More recent investigations have been conducted to provide comparison information about the relative efficacy and presence of side effects associated with these anticholinergic options (Amend et al. 2008; Stohrer et al. 2007). Stohrer et al. (2007) showed similarities in efficacy in a comparison study of propiverine vs oxybutynin that employed a double-blind, randomized, controlled study design. Both treatments significantly improved bladder capacity and reduced maximum detrusor pressure although fewer side effects (most notably dry mouth) were evident in subjects in the propiverine group. Of note, Amend et al. (2008) examined 3 combinations of anti-cholinergics in subjects (n=27) whose initial symptoms of incontinence did not completely resolve – even with dosages doubled from manufacturer recommendations (i.e., Horstmann et al. 2006). These authors added a second anti-cholinergic medication such that participants took either: 1) tolterodine / oxybutynin, 2) trospium / tolterodine or 3) oxybutynin / trospium and demonstrated that 85% of patients were treated successfully, despite having mostly unsatisfactory outcomes with a single medication. Each initial medication was maintained at thehigh (i.e., double dose) and there were no clear combinations that were superior to the other in terms of either effectiveness or side effect profile. It should be noted that there is a concern when administering doses of mixed anti-cholinergics for their potential consequences on heart rythm which would be detected with an electrocardiogram (ECG). Neither of studies reported conducting an ECG, which raises concerns about potential abnormalities and issues incurred by those receiving a mixed dose.

In addition, Kennelly et al. (2009) reported that a transdermal method of oxybutinin was effective in increasing the proportion of clean intermittent catheterizations without leaking as well as improving various urodynamic measures (e.g., reflex volume, amplitude of detrusor contraction, maximum bladder capacity, residual urine volume) in a pre-post investigation (n=24). These positive effects were seen and more importantly there were fewer side effects than typically seen with oral delivery, even at up to three times the standard dose.   

Conclusion

  • Level 1 evidence from two RCTs supports the use of propiverine in the treatment of detrusor hyperreflexia resulting in significantly improved bladder capacity, with one of these trials showing equivalent results to oxybutinin but fewer side effects, notably dry mouth.
  • Level 1 evidence from a single RCT supports the use of tolterodine vs placebo to significantly increase intermittent catheterization volumes and decrease incontinence in neurogenic detrusor overactivity.
  • Level 2 evidence from a small single open label prospective controlled trial that tolterodine and oxybutynin are equally efficacious in SCI patients with neurogenic detrusor overactivity except that tolterodine results in less dry mouth.
  • Level 4 evidence from single pre-post trials support the potential benefits of controlled-release oxybutynin as well as a transdermal system for oxybutinin administration, the latter with reduced side effect profile.
  • Level 4 evidence from a single study suggests benefits such as reduced incontinence and increased bladder capacity from combination treatments of two of oxybutinin, trospium or tolterodine, even in patients with unsatisfactory outcomes following a trial with one of these medications.
  • Level 1 evidence from a single RCT supports the use of trospium chloride to increase bladder capacity and compliance, and decrease bladder pressure with very few side effects in SCI individuals with neurogenic bladder.
  • Propiverine, oxybutynin, tolterodine and trospium chloride are efficacious anticholinergic agents for the treatment of SCI neurogenic bladder.

    Treatment with 2 of oxybutynin, tolterodine or trospium may be effective for the treatment of SCI neurogenic bladder in those not previously responding to one of these medications.

    Tolterodine, propiverine, or transdermal application of oxybutinin likely result in less dry mouth but are similarly efficacious to oral oxybutynin in terms of improving neurogenic detrusor overactivity.

Toxin Therapy for SCI-Related Detrusor Overactivity

Botulinum toxin A (BTx-A) has been used for many disorders including strabismus, focal spasticity, hyperhydrosis, cosmetic disorders (wrinkles) and others. A newly approved indication in the USA and Canada is for neurogenic detrusor overactivity treatment in individuals with SCI and multiple sclerosis. The advantage of botulinum toxin over systemic administration of medications such as anti-cholinergics is the botulinum toxin is used focally in the bladder, thus avoids systemic side effects for the most part. There are various types of botulinum toxin available, including various types of botulinum toxin type A. When evaluating the literature in this area, one must be aware that although Dysport and Botox are both derived from botulinum toin type A, they are very different and units cannot be compared or interchanged.

The use of capsaicin (CAP), a vanilloid, as a topical temporary analgesic is not uncommon as evidenced by over-the-counter ointments available for purchase in local pharmacies, and is used in the form of a topical patch for allodynia pain in Europe. Capsaicin induced localized and reversible antinociception by capsaicin is a result of induced C-fibre conduction and subsequent neuropeptide release inactivation (Dray 1992). Although C-fibers are not involved in normal voiding, neuroplastic changes to C-fiber bladder afferent growth account for injury emergent C-fiber mediated voiding reflex (i.e., spinal detrusor hyperreflexia; deGroat 1995). Resiniferatoxin (RTX) is another vanilloid which has been studied for its similar beneficial effects, with less irritation to the bladder and is thus better tolerated. By chemically decreasing C-fiber bladder afferent influence with intravesical vanilloids (i.e., CAP, RTX) bladder contractility is decreased and bladder capacity is increased (Evans 2005). 

Table: Toxin Therapy for SCI-Related Detrusor Overactivity

Discussion

Botulinum toxin

In 2005, Schurch et al. published a trial evaluating the efficacy of onabotulinum toxin A (oBTX-A), Botox, injections into the detrusor muscle in people with SCI to reduce incontinence and increase bladder capacity. This landmark rigorous RCT evaluated botulinum toxin for neurogenic overactive bladder. The study evaluated the effects of 200 IU, 300 IU, or placebo injected into the detrusor wall. The results revealed a significant decrease in incontinence by about half for both oBTX-A groups, and a significant drop in maximum detrusor pressure. Baseline maximum detrusor pressures were 92.6cm H2O and 77.0 cm H2O in the 300 IU and 200 IU groups, respectively, and by 2 weeks had dropped to 41.0 cm H20 and 31.6 cm H20), respectively. Dramatic improvements were seen in cystometric capacity with baseline being 293 cc and 260cc in the 300 and 200 group respectively, and improving by 2 weeks to 479cc and 482 cc respectively. Mean reflex detrusor volume improved at 6 weeks in the 300 U oBTX-A group and at 24 weeks in the 200 U oBTX-A group (p<0.021). The significant improvements were mostly maintained out to 6 months, at which point the study follow-up was terminated - thus, the true duration of effect of the injection is unknown.

Ehren et al. (2007) studied a different form of abobotulinum toxin A (abBTX-A), Dysport, using 500 IU in a placebo controlled study. These authors also found improved continence, cystometric capacity, and decreased pressures. In addition, concomitant anti-cholinergic use, tolterodine, was found to be less in the botulinum toxin group.

Schurch and colleagues (2000) were also the first group to publish a large prospective trial on the use of onabotulinum toxin for neurogenic detrusor overactivity to improve incontinence and increase bladder capacity. This first trial was not placebo controlled, but given the impressive changes in objective measures such as urodynamic measures, it bears considerable significance. Pre-injection, the subjects had detrusor hyperreflexia and urge incontinence resistant to high-dose oral anticholinergic treatment and emptied their bladders by intermittent self-catheterization. By 6 weeks post injection, ninety percent of subjects were continent between catheterizations in conjunction with markedly decreased or withdrawn anticholinergic drug administration. Post-void residuals were significantly increased, which is the goal with people on intermittent catheterizations, and significant increases in cystometric bladder capacity as well as decreases in maximum detrusor voiding pressure were found. Autonomic dysreflexic hypertensive crises were abolished in the 3 patients with a history of autonomic dysreflexia. This group reported that a dose of 300 units of oBTX-A was required for successful treatment of detrusor overactivity lasting at least 9 months per injection. These results were amplified by a large scale study (n=200 - 167 with SCI) involving a retrospective case series design across 10 European centres (Reitz et al. 2004). This study showed significant improvements in a wide variety of urodynamic-related measures that were maintained for up to 36 weeks following a single procedure of botulinum toxin injections to the detrusor. Several smaller open-label studies have had similar promising results (Hajebraimi 2005, Klaphajone 2005, Patki 2006, Tow 2007, Akbar 2007, Kuo 2008, Grosse 2009, Giannantoni et al. 2009). In all of these studies, incontinence was reduced and bladder capacity increased with botulinum toxin. The unique aspects of each of these will be noted below.

Klaphajone (2005) addressed the question of low compliance bladders in people with SCI. People with poor bladder compliance had been excluded in previous large trials. In this open-label trial, the authors found that bladder compliance, bladder capacity, and reflex detrusor volume all increased and maximum detrusor pressure decreased. However, most of these effects were only seen out to 16 weeks and not to 36 weeks (or longer) as has been shown in other studies in people with compliant but spastic bladders. An evaluation between these two points of 16 weeks and 36 weeks would have been helpful to learn how long to expect effects to last in this type of neurogenic bladder.

Abobotulinum toxin, at 1000 IU, was similiarly found to have beneficial effects (Patki 2006) in an open-label trial of 37 people with SCI and drug resistant neurogenic detrusor overactivity. At mean follow up of 7 months the maximum cystometric capacity, maximal detrusor pressure, quality of life and incontinence were significantly improved, and 86% were able to stop anticholinergics.

In 2006, Kuo evaluated the effects of suburothelial injections of onabotulinum toxin A instead of intradetrusor muscle injection, in hopes of reducing risk of urinary retention in those with neurogenic bladder dysfunction who continue to exhibit voiding dysfunction (frequency, urgency, and incontinence). The proposed mechanism for effect is addressing the afferent system with known effects on the P2X3 and TRYP V1 receptors, thus presumably decreasing the reflexic activity by targeting these receptors on the afferent loop. These subjects were not on intermittent catheterization at time of enrolment although perhaps some should have been as 58% of the people with SCI had baseline post-void residual values of >150ml at baseline. Only 8/24 of the subjects had SCI, and were incomplete or complete, with levels from C6-S2. Similar beneficial effects to the other studies were seen, with 92% of subjects with SCI becoming continent, but post-void residual increased by 4 times the baseline value. Thus, although the goal of subendothelial injections was to reduce the degree of urinary retention, this goal was not achieved, and no additional benefits were seen over those seen in studies with intra-muscular injection. Head to head comparisons would be required to indicate which type of injection is better. Certainly one cannot conclude from this study that suburothelial injections protect against worsening urinary retention.

Tow et al. (2007) assessed onabotulinum toxin in an open-label fashion and added frequency of catheterizations to the outcomes. This was significantly improved at the 6 week point but not at 24 weeks. Other measures seen in the previous studies were similarly improved, but this study, as did the 2000 Schurch study, followed subjects for 9 months. Only the improvement in catheterized volumes was maintained to the 9 month mark, while most of the other improvements persisted only until the 6 month mark. This study was small (n=15) and not placebo controlled. Perhaps the reason for not reaching statistical significance for changes out to 9 months was small sample size, as Schurch et al. (2000) did find many of these same parameters attained significance at 9 months.

Giannantoni et al. (2009) prospectively followed 17 persons with motor complete SCI and bladder dysfunction due to neurogenic detrusor overactivity over a period of 6 years as they were treated with 300U of intravesical onabotulinum toxin with re-injections as required. In addition to the prolonged follow-up period, which showed continued effectiveness and minimal side effects associated with ongoing treatment, this investigation incorporated an assessment of incontinence-related quality of life. Improvements in this measure were maintained throughout the treatment period.

Akbar et al. (2007) used abobotulinum toxin in an open-label fashion with the objective of reporting effects of repeated use of botulinum toxin to the detrusor. Some of these patients had systemic weakness after injections of 1000 IU, but when reducing the dose to 750 IU this side effect subsided. The subjects were reinjected with abobotulinum when their symptoms returned or when urodynamic studies revealed a return to baseline. The repeat injections were 7.8-8.0 months apart for the first 3 injections, then 9 months for the subsequent injection, although fewer patients continued in the study to this point (11 as compared to 41 receiving 3 injections). Compliance, maximum detrusor pressure, and capacity all improved significantly with respect to baseline with all reinjections. All these numbers showed a slight gradual improvement with each subsequent injection, but statistical analysis was not performed to show if this modest improvement was significant. The same results were found in a more recent retrospective case series where the treatment was botulinum toxin type A (Pannek et al. 2009). Notably, this study was the first to indicate decreased detrusor contractility in patients may occur with repeated injections (Pannek et al. 2009).

Hori (2009) addressed patient satisfaction with detrusor injections of botulinum toxin A by way of a 5-minute questionnaire conducted via telephone. Ninety percent of people who had botulinum toxin A injections for neurogenic detrusor overactivity stated they would consider staying on this treatment long-term. This group has had a low annual withdrawal rate from this long-term treatment and a high annual new patient starting rate, prompting the authors to conclude that health care systems would be advised to incorporate this new treatment option as part of routine service provision.

A retrospective trial (Grosse 2009) compared the effects of abobotulinum toxin in doses 500-1000 IU to onabotulinum toxin in doses 200-400 IU. The different doses of abobotulinum toxin had no difference at follow up of 3.8 months, and comparison of the abobotulinum toxin group to the onabotulininum toxin group revealed no difference at 3 months. Although the effect lasted 9.5 months in the abobotulinum toxin 500 group compared to 16.1 months in the abobotulinum toxin 1000 group, this was not judged to be statistically significant, but seems to have clinical significance. The difference does raise the question of whether larger dosing may have longer lasting effects, and certainly has potential for future studies. Note in this study 9/28 in abobotulinum toxin group did not respond compared to 7/28 in the onabotulinum toxin group. One subject who received abobotulinum toxin 750 IU experienced transient hypoasthenia.

Capsaicin

deSeze et al. (1998) has provided level 1 evidence in support of the ability of CAP to improve bladder function (decrease frequency and leakages) by increasing bladder capacity. These authors found that 30 days after instillation, CAP was superior to placebo in decreasing 24h voiding freq (p=0.016), decreasing 24h leakages (p=0.0008), increasing maximal cystometric capacity (p=0.01), and decreasing maximal detrusor pressure. However, these differences were not significant and they found similar side effects in each group. This study offers soe support to other small, non-RCT studies that reported significant CAP-induced increases in bladder capacity (Das et al. 1996; Dasgupta et al. 1998).

George et al. (2007) reported use a one time instillation and reported that the “efficacy” of cystometric capacity was significant. However, when evaluating the data, it seems the significant difference was actually a significant decline in capacity at 3 hours (pre=224.6 cc, 3 hr post=139.6 cc, p=0.015) and a non-significant decline at 1 week (174.2 cc at 1 week, p=0.059). The authors claim that there was a marked, progressive and overall improvement following capsaicin except for leak point pressure. But the statistical results do not support this claim, and only leak volume was improved statistically at 2 weeks. Autonomic dysreflexia, a significant side effect, was reported in 2 patients following CAP. Although this study included blinded evaluations of oxybutynin vs propantheline instillation, CAP evaluations could not be blinded and therefore, discussion of oxybutynin vs propantheline results were undertaken separately.

The Dasgupta group (1998) confirmed presence of metaplasia, dysplasia, and flat carcinoma in situ after treatment with Intravesical capsaicin.  All biopsies were determined to be benign but some showed signs of chronic inflammation. However, neither papillary nor solid invasive cancer was detected after 5 years of follow-up. Further surveillance is required up to 10 years when chemical carcinogenic morphologies typically present.

Resiniferotoxin

deSeze et al. (2004) established that RTX was similarly effective in increasing bladder capacity when compared to CAP. CAP was significantly more effective at increasing urgency delay (p<0.01) but there was only a trend to greater maximum bladder capacity in favour of CAP. There was also a statistically significant increase with CAP, suprapubic pain, although it was clinically tolerable and brief (p<0.04). The increase in persistent clinical improvements due to RTX over CAP at 90 days follow-up was not statistically significant.

The efficacy of RTX vs placebo was confirmed in an RCT conducted by Silva et al. (2005) where they found that RTX was responsible for significantly increased volume of first involuntary detrusor contraction (FDC; 143±95mL vs184±93mL; p=0.03), maximum cystometric capacity (MCC; 115±61mL vs 204±92mL; p=0.02), decreased urinary frequency (p=0.01) and incontinence (p=0.03) with similar side effects as compared to placebo. Kim et al. (2003) confirmed the improvements in SCI bladder function and further investigated the effect of dose (single 100 ml instillation of 0.005, 0.025, 0.05, 0.10, 0.2, 0.5, 1.0 microM RTX or placebo). Despite the small sample size in each dose category, MCC increased by 53% and 48% for the two highest dosages by 3 weeks post-treatment. Similarly, incontinence episodes decreased by 51.9% and 52.7%.

Nociception/orphanin phenylalanine glutamine

Nociception/orphanin phenylalanine glutamine (N/OFG) is a heptadecapeptide (Meunier et al. 1995; Reinscheid et al. 1995) that acts on sensory innvervation of the lower urinary tract in a similar fashion to CAP and RTX. It activates the G protein coupled receptor nociceptin orphan peptide and thus has an inhibitory effect on the micturition reflex in the rat (Lecci et al. 2000). Following a successful preliminary human study, Lazzeri et al. (2003) confirmed that N/OFG versus placebo is responsible for a significant increase in bladder capacity (p<0.001) and threshold volume of detrusor overactivity (p<0.001), and a non-significant decrease of maximum bladder pressure of the dysfunctional neurogenic bladder. These results were verified in an additional small-scale RCT (n=18) of a 10 day course of N/OFG treatment vs placebo (saline). Statistically significant improvements to bladder capacity (assessed by daily voiding diary) and urine leakage episodes were seen in the treated group but not with placebo (Lazzeri et al. 2006). The authors conclude that this inhibition of the micturition reflex supports nociceptin orphan peptide receptor agonists as a possible new treatment for neurogenic bladders of SCI patients.

Conclusion

  • Level 1 evidence based on two RCTs supports the use of Onabotulinum toxin A injections into the detrusor muscle to provide targeted treatment for neurogenic detrusor overactivity and urge incontinence resistant to high-dose oral anticholinergic treatments with intermittent self-catheterization in SCI. Numerous level 3 and 4 studies confirm the efficacy and safety.
  • Level 4 evidence based on a single case series indicates detrusor contractility may be decreased through repeated BoNT-A injection, though prospective study and higher levels of evidence is needed to confirm.
  • Level 1 evidence supports the use of vanillanoid compounds such as capsaicin or resiniferatoxin to increase maximum bladder capacity and decrease urinary frequency and leakages in neurogenic detrusor overactivity of spinal origin.
  • Level 4 evidence exists to suggest that intravesical capsaicin instillation in bladders of SCI individuals does not increase the rate of common bladder cancers after 5 years of use.
  • Level 1 evidence based on two small-scale RCTs supports the use of N/OFG, a nociceptin orphan peptide receptor agonist for the treatment of neurogenic bladder in SCI.

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 under toxins, but in fact may also be administered as an intravesical instillation. Other medications used in this manner are the 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 intermittent catheterization, then leaving it in place until the next scheduled intermittent catherization. 

Table: Intravesical Instillations for SCI-Related Detrusor Overactivity

Discussion

George et al. (2007) described results with a pre-post trial with both propantheline and oxybutynin. This group also reported effects of capsaicin, but will not be reported as comparative data here due to the different treatment schedule used for capsaicin. Unfortunately, the data is not compared directly between propantheline and oxybutynin, as it was noted that overall the treatments resulted in a significant decrease in leak volume and leak frequency with no significant change in cystometric capacity, leak point pressures and intermittent catheterization volumes. In separate evaluations of propantheline and oxybutynin, it seems only propantheline resulted in significant change in leak frequency, and all other parameters were not changed for either medications before and after therapy. Two of the patients with the oxybutynin instillations developed systemic side effects (e.g., dry mouth) typical of those on oral medications.

Vaidyananthan et al. (1998) reported a pre-post trial (n=7) for which individuals originally managed by condom catheterization were switched to intermittent catheterization for a period of time, followed by another period when an intra-vesical instillation of oxybutynin was also administered. Although no group statistical results were reported, all subjects showed improved continence with intermittent catheterization and even more so when oxybutynin was added. Quality of life scores were mixed with intermittent catheterization alone but showed a definite improvement when oxybutynin was added. This may have been partly due to a reduced incidence of UTIs with the combination of intermittent catheterization and intra-vesical oxybutynin. The real implications of the instillations of oxybutynin alone are not known from this study.

Singh and Thomas (1995) presented a pre-post study with oxybutynin instillations, and were unable to show any significant improvements. Ersoz et al. (2010) challenge these results however by showing a significantly improved bladder volume for patients using indwelling catheters who are treated simultaneously with oral and intravesical oxybutynin. In this study, however, 52.6% of patients were lost to attrition and reports of intravesical instillation of oxybutynin were common (Ersoz, 2010). Given the equivocal results noted in most studies (e.g., lack of effect and presence of possible systemic side effects) and difficulty in administering treatment, caution is warranted in considering intra-vesical instillation of oxybutynin. When performed, combined oral and intravesical instillation may be preferred.

Conclusion

There is level 4 evidence from 3 studies that instillations with oxybutinun or propantheline have equivocal benefits for neurogenic bladder in people with SCI. There is level 4 evidence from1 study that combined oral and intravesical installation of oxybutinin significantly improves bladder volume. There is level 4 evidence suggesting systemic absorption may occur with this therapy, resulting in systemic side effects.

  • Intravesical instillations with oxybutinun or propantheline alone are ineffective for treating neurogenic bladder in people with SCI.

Other Pharmaceutical Treatments for SCI-Related Detrusor Overactivity

There are other therapies reported to decrease neurogenic detrusor overactivity that have not been mentioned nor fit into the categories noted above. In particular, medications that have been traditionally used for treating spasticity of skeletal muscles in spinal cord injury, i.e., intrathecal baclofen and intrathecal clonidine, have been reported to be helpful in the area of decreasing spasticity of the bladder in the same population. Intrathecal therapy has been used since the early 1990’s for treating spasticity, and better spasticity control can be achieved with fewer systemic side effects as compared to oral administration

Table: Intrathecal Baclofen and Clonidine for SCI-Related Detrusor Overactivity

Discussion

Chartier-Kastler et al. (2000) specifically used test bolus intrathecal injections of clonidine (ITC) to investigate its effects on SCI neurogenic detrusor overactivity, in patients otherwise resistant to a combination of oral treatment and self-clean intermittent catheterization (SCIC). After the test bolus injection, 6 of 9 subjects elected to have permanent pump implantation for the treatment of severe detrusor overactivity. Further confirmatory study of this proposed alternative treatment is needed as the sample size was small and no objective outcome measures were used.

Steers et al. (1992) investigated the use of intrathecal baclofen (ITB) specifically for the treatment of genitourinary function in 10 SCI patients with severe spasticity. Compared with placebo, involuntary bladder contraction induced incontinence was eliminated and 1 patient was able to convert from indwelling urethral catheterization to intermittent self-catheterization. Bladder capacity was increased by a mean of 72% while detrusor-sphincter dyssynergia was eliminated in 50% of patients. These authors recommend the use of ITB for SCI genitourinary dysfunction when oral pharmacological interventions are insufficient to improve bladder function. However, in light of the documented effectiveness of Botulinum toxin described above, the relative ease and temporary nature of treatment with Botulinum toxin, and the absence of significant adverse effects, it is unlikely that clinicians would chose intrathecal treatments over toxin therapy except in cases when intrathecal therapy is required for other problems (eg. spasticity)

Conclusion

  1. There is level 1 evidence from a single small RCT (n=10) that intrathecal baclofen may be beneficial for bladder function improvement in individuals with SCI when oral pharmacological interventions are insufficient.
  2. Level 4 evidence is available from a single, small (n=9), case series study for the use of intra-thecal clonidine to improve detrusor overactivity in individuals with SCI when a combination of oral treatment and sterile intermittent catheterization are insufficient.
  • Intrathecal baclofen and clonidine may be beneficial for bladder function improvement but further confirmatory evidence is needed.

Enhancing Bladder Volumes Non-Pharmacologically

Electrical Stimulation to Enhance Bladder Volumes

Electrical stimulation, most notably anterior sacral root stimulation, has been used to enhance bladder volume and induce voiding (Egon et al. 1998; Brindley et al. 1982). Typically, this approach has involved concomitant dorsal sacral rhizotomy and implantation of a sacral nerve stimulator. The combined effect of this is a more compliant bladder with more storage capacity under lower pressure and triggered voiding resulting in reduced incontinence, without the need to catheterize. As the focus of many of the studies involving electrical stimulation is on both of these functions (i.e., increased bladder capacity and control of bladder emptying), we will describe the evidence for these and other methods of electrical stimulation for improving bladder outcomes in a single subsequent subsection (see Section 13.3.4.7 Electrical Stimulation for Bladder Emptying (and Enhancing Volumes)). 

Surgical Augmentation of the Bladder to Enhance Volume

Bladder augmentation or augmentation cystoplasty is a surgical repair to the bladder typically suggested when conservative approaches such as anticholinergics with intermittent catheterization have failed to create an adequate bladder volume under low pressure for storage (Chartier-Kastler et al. 2000; Quek & Ginsberg 2003). Intolerable incontinence, renal deterioration, and/or local erosions or infections related to the use of catheters are common final pathways that may lead the clinician to consider definitive urological surgery. There are several approaches that have been described in the SCI literature with a common method being variations of the “clam-shell” ileocystoplasty in which the bladder is opened up like a clam and isolated intestine (ileum) are patched in to create a larger bladder (Chartier-Kastler et al. 2000; Nomura et al. 2002; Quek & Ginsberg 2003; Chen & Kuo, 2009). Surgical techniques that are focused on urinary diversion away from the bladder and subsequent drainage (e.g., cutaneous ileal conduit diversion) are discussed in the section on incontinent urinary diversion in the section that is focused on drainage (see 13.3.4.6 Continent Catheterizable Stoma and Incontinent Urinary Diversion).

Table: Surgical Augmentation of the Bladder to Enhance Volume

Discussion

As is the case for most surgical approaches, the evidence for surgical augmentation of the bladder exists in the form of clinical experience from individual centres as is described in retrospective chart reviews (e.g., Nomura et al. 2002; Quek & Ginsberg 2003; Chen & Kuo 2009; Reyblat et al. 2009) or more rarely may be found in prospective studies that are limited to non-controlled, non-randomized pre-post (cohort) study designs (e.g., Chartier-Kastler et al. 2000). Long-term retrospective results associated with ileocystoplasty in persons with traumatic and non-traumatic SCI (or spina bifida) were reported over a mean period of 5.5 and 8 years by Nomura et al. (2002) (n=21) and Quek and Ginsberg (2003) (n=26) respectively. Chartier-Kastler et al. (2000) conducted a prospective evaluation of 17 persons with traumatic longstanding SCI who underwent enterocystoplasty (i.e., ileocystoplasty) with systematic follow-up at 1, 3, 6, 12 months and then yearly for a mean follow-up of 6.3 years. Chen & Kuo (2009) reported on 40 adults with SCI. In all cases, this was conducted in individuals with overactive bladder and/or detrusor-sphincter dyssynergia with reflex incontinence which failed to respond to conservative treatment. Across all these studies, at follow-up, bladder capacity increased dramatically with near or complete resolution of incontinence in the vast majority of patients. Chartier-Kastler et al. (2000) conducted systematic urodynamic investigations and showed a significant increase in maximal cystometric capacity by 191% (174.1 to 508.1 ml, p<0.05) with a concomitant decrease in maximal filling pressure of 72% (65.5 60 18.3 cm H2O, p<0.05). These results are similar to those reported by Nomura et al. (2002) and Quek and Ginsberg (2003). Reyblat et al. (2009) compared an “extraperitoneal” approach (small peritoneotomy and standard ‘clam’ enteroplasty) vs. the standard intraperitoneal approach in which the extraperitoneal approach was found to result in shorter operative time, shorter hospital stay, and eventual return of bowel function. No serious complications were noted across the studies, and other complications were noted in only a few individuals (e.g., transient paralytic ileus, vesicoureteral reflux, wound infection, urethral stricture of unknown cause, recurrent pyelonephritis possibly due to non-compliance with intermittent catheterization and use of Crede maneuver) with the vast majority of these responding well to conservative treatment (Chartier-Kastler et al. 2000; Nomura et al. 2002; Quek & Ginsberg 2003). Subsequent subjective assessment of patient satisfaction with the procedure was reported to be extremely high (Quek & Ginsberg 2003) which is consistent with other similar investigations in SCI patients (Khastgir et al. 2003). Chen & Kuo (2009) noted, however, that issues with UTI, reservoir calculi and new onset upper-tract urolithiasis that commonly follow the ileoplasty still require resolution. Reyblat et al. (2009), in a retrospective chart review, reported equivocal postoperative continence using an extraperitoneal (small peritoneotomy and standard ‘clam’ enteroplasty) vs. the standard intraperitoneal augmentation. The extraperitoneal approach resulted in shorter operative time, shorter length of stay, and ore rapid return of bowel function. There was a potential for selection bias in this study that was mitigated with a subgroup analysis in an effort to control for a significant confounding variable of higher rates of prior abdominal surgery in the intraperitoneal group (Reyblat et al. 2009).

Conclusion

  • There is level 4 evidence from four studies that surgical augmentation of bladder (ileocystoplasty) may result in enhanced bladder capacity under lower filling pressure and improved continence in persons with SCI who previously did not respond well to conservative approaches for overactive bladder.
  • There is level 3 evidence from a single study that extraperitoneal (vs intraperitoneal) augmentation enterocystoplasty produces equivocal postoperative continence with easier early postoperative recovery.
  • Surgical augmentation of bladder may result in enhanced bladder capacity under lower filling pressure and improved continence in persons with SCI.

    Extraperitoneal vs intraperitoneal augmentation enterocystoplasty may result in better postoperative recovery.

Enhancing Bladder Emptying Pharmacologically

As noted previously, normal voiding process occurs through a pathway between the pontine and sacral micturition centers. These centers work synergistically to allow for bladder storage or drainage. However, in individuals with SCI lesions this process can be interrupted. This causes impairment of voiding function, which can be classified into two categories: impairment in storing and impairment in emptying (Hanno 2001).

Enhancing bladder storage, as discussed earlier in the chapter, involves relaxing the detrusor muscle and allowing for increased bladder volumes. Individuals with impairment of bladder emptying are those whose sphincter is unable to relax or who have weak or nonexistent detrusor muscle contractions, both causing failure to empty. These individuals can be treated pharmacologically with oral alpha adrenergic blockers and botulinum toxin (injected into the sphincter). Both interventions are intended to improve voiding but also may increase the tendency towards incontinence, a point not highlighted in the studies presented below. However, in those male patients who already have incontinence, and are using condom drainage, but have persistently elevated residuals, alpha blockers or Botulinum toxin (injected into the sphincter) may result in more complete emptying.

Alpha-adrenergic Blockers for Bladder Emptying

A variety of alpha adrenergic blockers have been used to treat SCI bladder dysfunction. These drugs have been used to target alpha adrenoreceptor blocker subtypes which may be implicated in a variety of mechanisms including bladder neck dysfunction, increased bladder outlet resistance, detrusor-sphincter dyssynergia, autonomic hyperreflexia or upper tract stasis.

Table: Summary of Alpha Adrenergic Blockers

Discussion

Tamsulosin is an alpha1 adrenoreceptor antagonist that has been used to treat SCI bladder neck dysfunction by causing smooth muscles in the bladder neck to relax and improve urine flow rate. A large scale (n=263) study conducted by Abrams et al. (2003), provided evidence for decreased micturition frequency and improvement in urinary leakage parameters for individuals with SCI. This study consisted of a 4 week RCT followed by a longer-term open-label period conducted over a year in persons with overactive bladder with or without dyssynergia. Maximal urethral pressure determined via urethral pressure profilometry was reduced significantly with the longer-term trial (p<0.001) although only a trend was apparent during the one month RCT with 0.4 mg dose (p=0.183) but not with a dose of 0.8 mg (p=0.443). In the 1 year open-label investigation tamsulosin also was associated with several improved cystometry parameters related to bladder storage and emptying, and also resulted in increased mean voided volume values as reported in a patient diary. Given that most positive outcomes were more apparent with the open-label phase, which consisted of a pre-post trial design, this trial has been assigned as level 4 evidence.

Moxisylyte is an alpha adrenoreceptor blocker used commonly in the treatment of Raynaud’s disease where narrowing of the blood vessels in the hands causes numbness and pain in the fingers. Costa et al. (1993) in an n=20 RCT investigated the off-label use of moxisylyte in the treatment of SCI bladder neck dysfunction. With its smooth muscle relaxant property, the decrease in urethral closure pressure was found to be dose related and significant when compared to placebo, with the maximum reduction of 47.6% occurring at 10 minutes after 0.75mg/kg in individuals with SCI.

Terazosin is often used to treat hypertension. However, this alpha-adrenergic blocker is also useful in treating bladder neck dysfunction by relaxing the bladder neck muscles and easing the voiding process. Perkash (1995) reported that although 82% of patients (N=28), with absent detrusor sphincter dyssynergia, perceived improvement in voiding; only 42% registered meaningful objective decreases in maximum urodynamic voiding pressure. Side effects, tolerance and required additional urodynamic monitoring may be deterrents to the wide-spread adoption of terazosin as an alternative treatment for bladder neck dysfunction in SCI individuals. The specificity of terazosin action on the bladder neck, exclusive of the external sphincter, was demonstrated by Chancellor et al. (1993) in a subgroup of SCI patients who had persistent voiding difficulty after previous sphinterotomy subsequent to failed initial terazosin treatment.

Phenoxybenzamine is an antihypertensive usually chosen to treat autonomic symptoms of pheochromocytomas such as high blood pressure or excess sweating. Al-Ali et al. (1999) undertook to utilize the autonomic effects of phenoxybenzamine to treat bladder dysfunction which is in part under autonomic control. Treatment with phenoxybenzamine (n=46 with 41 completers) resulted in a reduction of bladder outlet resistance, detrusor-sphincter dyssynergia or autonomic hyperreflexia in some subjects while no benefits were recorded for areflexive bladders. Phenoxybenzamine can be beneficial as an adjunct treatment for neuropathic bladder following SCI, when tapping or crede is unable to achieve satisfactory residual urine volumes of <100 mL. The lack of efficacy in those with bladder neck dysfunction was specifically noted in this study. Since statistically significant results were not reported in this study, further appropriately sized RCTs would be helpful in providing sufficient evidence for the use of phenoxybenzamine in the treatment of SCI neuropathic bladder.

The pyelouretheral smooth muscle responsible for urethral peristalsis and movement of the urine from the kidneys to the bladder via the ureters is also a potential site of action for alpha 1-receptor antagonist therapy. Linsenmeyer et al. (2002), in a small (n=10) retrospective chart review found that in men with upper tract (i.e. kidneys and ureters) stasis secondary to SCI at or above T6, 6 months of alpha1-blocker therapy provided improvement in upper tract stasis in 80% of subjects who used reflex voiding to manage their bladder as measured by significant decreases of the duration of uninhibited bladder contractions. Firm conclusions about effectiveness and the optimum duration of treatment can only be validated with further RCT trials.

Conclusion

  • Level 1 evidence from a single study suggests that moxisylyte decreases maximum urethral closure pressure by 47.6% at 10 minutes after an optimum dose of 0.75mg/kg in individuals with SCI.
  • There is level 4 evidence from a single study that suggests that tamsulosin may improve bladder neck relaxation and subsequent urine flow in SCI individuals.
  • There is level 4 evidence (two studies, n=28 & 9) that supports terazosin as an alternative treatment for bladder neck dysfunction in SCI individuals provided that side effects and drug tolerance are monitored.
  • There is level 4 evidence derived from a single, case series study involving 46 subjects (41 completers) that indicates some potential for phenoxybenzamine as an adjunct treatment for neurogenic bladder following SCI, when tapping or crede is insufficient to achieve residual urine volume of <100mL. Further evidence is required.
  • Level 4 evidence from 1 small retrospective chart review suggests that 6 months of alpha 1-blocker therapy may improve upper tract stasis secondary to SCI in men by decreasing the duration of involuntary bladder contractions.
     
  • Tamsulosin may improve urine flow in SCI individuals with bladder neck dysfunction.

     

    Mosixylyte is likely able to decrease maximum urethral closure pressure at
    a dose of 0.75mg/kg in individuals with SCI.

     

    Terazosin may be an alternative treatment for bladder neck dysfunction in individuals with SCI. but side effects and drug tolerance should be monitored.

     

    Phenoxybenzamine may be useful as an adjunct therapy for reducing residual
     urine volume in SCI neuropathic bladders maintained by crede or tapping.

     

    Six months of alpha 1-blocker therapy in male SCI patients may improve upper tract stasis.

Botulinum Toxin for Bladder Emptying

Botulinum toxin is an exotoxin produced by the bacteria Clostridium botulinum. As noted previously (see 3.1.2 Toxin therapy for SCI-related Detrusor Overactivity), it has been used for many conditions associated with muscular overactivity and specifically for neurogenic detrusor overactivity. In SCI individuals with sphincter overactivity causing drainage impairment, botulinum toxin may also be administered into the external urethral sphincter causing the muscle to relax resulting in improved drainage (deSeze et al. 2002). The toxin works by inhibiting acetylcholine release at the neuromuscular junction and relaxing the muscle, an effect that gradually wears off over the months following injection. Injections of botulinum toxin A into the sphincter may improving emptying and, if possible, eliminate the need for catheterization for some individuals with neurogenic bladder. 

Table: Bladder Emptying through Botulinum Toxin

Discussion

DESD and associated high bladder pressures, vesicoureteral reflux, and frequent UTI are associated with poor long-term outcomes for patients. These patients may develop upper tract deterioration and/or suffer incontinence and poor quality of life. Injection into the external urethra with botulinum toxin has been shown to reduce bladder pressures, improve incidence of UTI, and in some patients, normalize bladder emptying (Tsai et al. 2009, Kuo 2008). The important impact of increased incontinence after sphincter injection, along with urodynamic parameters were studied by Kuo. While this author cautions that QoL can decrease due to the increased incontinence experienced by some individuals, careful patient selection may allow some to benefit from the clearly evident improvement in urodynamic parameters and UTI incidence. Tsai et al. (2009) showed statistically significant improvement in quality of life post injection, but did not reveal data on incontinence.

The improvement found in post voiding residual volume demonstrated by the Kuo and Tsai studies was initially shown in the study by deSeze et al. (2002) who conducted a randomized, controlled, double blind study using lidocaine as a control injection (n=8) compared to botulinum toxin A (BTxA) as the active treatment (n=5). This study found BTxA improved post void residual volume in individuals with SCI significantly better than lidocaine. One month after BTxA was injected into the external sphincter, post-voiding residual volume decreased significantly by 159.4 mL to 105.0 mL and all patients who previously presented with autonomic dysreflexia no longer exhibited symptoms.

Other studies also showed a decrease in symptoms of autonomic hyperreflexia in at least 60% of patients (Tsai et al. 2009, Kuo 2008, Dykstra et al. 1988; Dykstra & Sidi 1990; Petit et al. 1998; Schurch et al.1996). Almost all patients showed post-injection sphincter denervation on electromyography; resulting in temporary relief of these symptoms for about 2-3 months leading to the need for subsequent BTxA injections to maintain results (Dykstra et al. 1988; Dykstra & Sidi 1990).

Schurch et al. (1996) compared the effectiveness of transurethral versus transperineal botulinum toxin A injections through a prospective controlled study.  The study found that transurethral botulinum toxin injections were significantly more effective in reducing urethral pressure than transperineal injections. However, other symptoms were improved through either injection method. Tsai in 2009 described a method of transperineal sphincter injections using fluoroscopic guidance and EMG that resulted in excellent effects on bladder emptying, with most patients returning to voiding. Patients were able to avoid frequent intermittent catheterization, and three patients were able to discontinue indwelling catheterization altogether.

Schurch et al (1996) also revealed the additive effects of recurrent BTx injections resulting from prolonged inhibition of acetylcholine release. After 3 monthly injections, the therapeutic effects of BTx lasted for as long as 9 months compared to only 2 – 3 months with 1 injection.

Phelan et al. (2001) were the first to demonstrate the successful use of botulinum toxin A in women. This study of 13 females showed that all but 1 patient was able to spontaneously void after botulinum A injection. Women, as a result of anatomial differences, often have greater difficulty performing self-catheterization than do men. Therefore voiding “normalization” as a result of sphincter injection with botulinum toxin may have an even more significant role in the urologic management of females with SCI. More study on the long term outcome of “spontaneous voiding” after sphincter injection in women is required.

Chen et al. (2010) evaluated the effects of a single transrectal ultrasound (TRUS)-guided transperineal injection of 100U oBTX-A to the external urethral sphincter (EUS) to treat DESD. As the prostate gland represented a key landmark in the TRUS-guided injection, the study was limited to male subjects. Video-urodynamic results obtained at an average of 33.3 days postinjection showed significant reduction in dynamic urethral pressure, integrated electromyography (iEMG), and static urethral pressure. The oBTX-A injection did not produce a significant decrease in maximal detrusor pressure. This was the first study to demonstrate the effect of TRUS-guided transperineal oBTX-A injection into the EUS and the potential for achieving outcomes similar to transurethral injection.

While not specifically mentioned in the above studies, a group of patients likely to benefit from injections of BTx into the sphincter are those men who have persistently elevated bladder volumes while using condom drainage. Sometimes such patients have chosen condom drainage because of reluctance to perform self catheterization while other times this bladder drainage option is chosen because of persistent incontinence on intermittent catheterization regimes despite adequate trials of anticholinergic medication. These patients could theoretically benefit from improved drainage, as residual urine is a common cause of UTI, and can also accompany elevated bladder pressures, that put upper tracts at risk. Whether or not such patients actually resume “voiding” to allow for the discontinuation of condom drainage altogether has not been addressed.

Botulinum toxin therapy has the advantage of avoiding major surgical procedures and their associated risks. Botulinum toxin therapy injection relaxes the external sphincter resulting in a decrease in post-voiding residual urine volume, and in 70% of patients, acceptable voiding pressures (Tsai et al. 2009). This improvement further seems to result in decreasing other symptoms such as autonomic dysreflexia and UTI incidence. However, due to transient sphincter denervation, it has the disadvantage of requiring repeated injections to maintain its therapeutic results. Also, post injection urodynamic studies should be done to prove that resultant voiding pressures are in the acceptable range. For those individuals with SCI with neurogenic bladder that do not experience unacceptable incontinence, botulinum toxin injection into the external sphincter is effective in assisting with more effective bladder emptying. Whether or not recurrent sphincter injection related improvements in voiding pressure and UTI incidence results in better long term upper tract outcomes requires further study.  Furthermore, clarity over the patient characteristics best suited to maximize the benefits of sphincter injections without subsequent unacceptable incontinence is needed in future studies to ensure widespread clinical uptake.

Conclusion

There is level 1 evidence from a single RCT with support from several additional controlled and uncontrolled trials that botulinum toxin injected into the external urinary sphincter may be effective in improving outcomes associated with bladder emptying in persons with neurogenic bladder due to SCI.

  • Botulinum toxin injected into the sphincter is effective in assisting with bladder emptying for persons with neurogenic bladder due to SCI.

Other Pharmaceutical Treatments for Bladder Emptying

Beyond the typical Alpha adrenergic and botulinum toxin approaches to improving bladder emptying, other pharmaceutical interventions have been explored. While these approaches still total few in number, this section describes primarily the use of tadalafil (Taie et al. 2010), a phosphodiesterse-5 (PDE5) inhibitor (Taie et al. 2010) and 4-Aminopyridine, (Grijalva et al. 2010). 4-Aminopyridine prepared in various commercial formulations for the treatment of MS related walking difficulties is also known fampridine [ampyra, fampyra] Most SCI specific studies involving 4-Aminopyridine assess bladder sensation and/ or control with respect to outcomes relevant to bladder management; often conducting more global assessments of function following treatment. This section reports only on bladder specific outcomes.

Table: Other Pharmaceutical Treatments for Bladder Emptying

Discussion

With respect to bladder management, phosphodiesterase-5 inhibitors (PDE5) inhibitors are postulated to promote relaxation of the detrusor muscle, thereby decreasing overactivity and increase capacity and compliance. This was confirmed in work by Taie et al. (2010) in male participants with supra sacral SCI where bladder compliance and capacity increased, and maximum voiding detrusor pressure and filling pressure decreased significantly following a single dose of 20mg oral tadalafil. As the evidence in this area is limited to a single study, further research is warranted before recommending this treatment.

4-Aminopyridine is a potassium channel blocker, prolonging action potentials and increasing neurotransmitter release at the neuromuscular junction (NMJ). Only one study to date, Grijalva et al. (2010), has explicitly commented on bladder function following administration of fampridine. During the open-label portion of the study where dosage levels of fampridine peaked, 3/12 participants regained both sensation and control of the bladder sphincter, and 1/12 regained sensation only. The paucity of literature in this area does not yet warrant fampridine as a primary treatment of bladder management in SCI.

Conclusion

There is level 4 evidence from a single study that PDE5 inhibitors may be effective in improving outcomes associated with bladder emptying in persons with neurogenic bladder due to SCI.

There is level 4 evidence from a single study that 4-aminopyridine, at sufficient dosage, may be effective in restoring sensation and/ or control of the bladder sphincter.

  • A single dose of oral tadalafil is effective in improving urodynamic indices in males with supra sacral SCI; more evidence is needed to support this as a treatment option.

    4-Aminopyridine at sufficient dosage may return sensation and control of the bladder sphincter following SCI; more evidence is needed to support this as a treatment option.

Enhancing Bladder Emptying Non-Pharmacologically

Comparing Methods of Conservative Bladder Emptying

Bladder emptying must be conducted under low pressure conditions in order to prevent upper urinary tract complications which may lead to renal failure. The choice of bladder management method must also result in continence, be acceptable to the individual with neurogenic bladder, and facilitate the greatest independence. During rehabilitation, most people with SCI are evaluated and consulted for the most suitable bladder management technique, taught how to manage the chosen method, and are advised as to complications and alternatives. In order to counsel patients appropriately, it is helpful for the clinician to understand the data related to bladder management method and complications. The section below reviews several papers that review the outcome of groups of patients treated with the most commonly chosen conservative methods of bladder management. Further papers addressing outcomes are included in the indwelling and intermittent catheterization sections.

Management methods discussed with the patient initially are based on clinical problems – eg. incomplete emptying, incontinence, dysreflexia, etc.  – and on the functional ability of the patient. The conservative methods for bladder management include the following: Intermittent catheterization, indwelling urethral catheterization, or condom catheterization (males only). If bladder function permits, spontaneously “triggered” or expression voiding without the need for an external drainage system may also be an option, although the disadvantages with these approaches have been outlined in a review (Wyndaele et al. 2001). Suprapubic catheterization is occasionally chosen in the subacute period given that there is no disturbance to the urethra.  However, the complication rate remains high for this invasive technique and thus it becomes a more suitable option in the chronic period.  Urodynamic studies provide information on bladder storage and emptying pressure, presence of reflux, and are essential in the management of the patient as the data is useful in influencing the choice of bladder management method.  Whether or not, and why, patients change their bladder management method are also topics of importance. Green (2004), Drake et al. (2005), and Yavuser et al. (2000), address these issues, listing some of the common complications as reason for change:  frequent UTI’s, upper tract deterioration, increased post void residual urine volume, bladder or kidney stones, functional decline and patient request. The section below presents data on retrospective studies which attempt to clarify the type and incidence of complications associated with the above methods of bladder management. For the most part, these approaches are considered in advance of other options involving bladder augmentation surgery or stimulator implantation, subjects of later sections.

Table: Comparison Studies of Conservative Bladder Emptying

Discussion

Several authors have examined the frequency of a variety of urological and renal complications associated with various forms of chronic bladder management (Ord et al. 2003; Weld & Dmochowski 2000; Hackler 1982). These authors have all employed retrospective chart reviews to examine complication rates associated with long-term follow-up data. In general, these authors concur that the greatest numbers of complications occur with long-term use of indwelling suprapubic and urethral catheters. In particular, of these investigations, Weld and Dmochowski (2000) employed a large sample (N=357) and examined the greatest range of complications. These authors noted that long-term urethral catheterization was associated with the largest overall number of complications, with long-term suprapubic catheterization ranked next. Depending on the specific complication, one of these two methods was associated with the highest incidence. Urethral catheter users had the highest rates for epididymitis, pyelonephritis, upper tract stones, bladder stones, urethral strictures and periurethral abscess. Suprapubic catheter users had the highest rates for vesicoureteral reflux and abnormal upper tracts. It should be noted that these authors did not account for changing bladder management methods, preferring to simplify the analysis by classifying the results by the most predominate bladder management method.

Ord et al. (2003), on the other hand, also examined a relatively large dataset (n=467) but examined all the combinations of changing methods. However, these authors limited their analysis to the effect of various bladder management techniques on the risk of bladder stone formation. Similar to Weld and Dmochowski (2000), these authors also found a slightly greater incidence of bladder stones for indwelling urethral catheterscompared to suprapubic catheters. Each of these methods, however, resulted in a greater incidence of bladder stones than intermittent catheterization. Ord et al. (2003) reported hazard ratios relative to intermittent catheterization of 10.5 for suprapubic catheters and 12.8 for indwelling urethral catheters. In contrast, Hackler (1982) reported comparisons between long-term complication rates among those with condom (Texas), urethral (Foley) and suprapubic catheterization and found markedly higher rates for those managed with suprapubic catheters even though the follow-up period for these patients was only 5 years as compared to 20 years for those managed with the other 2 methods. However, these findings reflected a much smaller series of patients (N=31) and the comparisons were made from patients from different time periods reflecting different “generations” of care.

It should be noted that even though the data favor intermittent catheterization or triggered spontaneous voiding, it is not always possible to use these methods. Lack of independence for catheterization can limit the use of intermittent catheterization in tetraplegics and in women, while spontaneous voiding may not be possible given the state of bladder function (Yavuzer et al. 2000). While every effort is made to start patients on intermittent catheterization programs, some patients change to other methods with time. Drake et al. (2005) reported a 28.8% incidence in change of bladder management method, while Yavuzer et al. (2000) found that up to 60% of patients changed from intermittent to indwelling catheter use. In Green’s Model System’s study (2004), only 25% changed to indwelling catheters over 15 years. The primary reasons indicated for changing methods were a greater dependence on care-givers than originally thought, presence of severe spasticity, incontinence and inconvenience with intermittent catheterization (females only). Thus assisting patients in choosing the most optimal method of bladder management is important. If less optimal methods of management are used post-injury, appropriate or increased surveillance must continue, given the described complication rates.  

Conclusion

There is level 4 evidence that indwelling urethral catheterization is associated with a higher rate of acute urological complications than intermittent catheterization. 

There is level 4 evidence that prolonged indwelling catheterization, whether suprapubic or urethral, may result in a higher long-term rate of urological and renal complications than intermittent catheterization, condom catheterization or triggered spontaneous voiding. 

There is level 4 evidence that intermittent catheterization, whether performed acutely or chronically, has the lowest complication rate. 

Results are conflicting about the complications associated with chronic use of spontaneous triggered voiding but some authors present level 4 evidence that this method has comparable long-term complication rates to intermittent catheterization.

There is level 4 evidence that those who use intermittent catheterization at discharge from rehabilitation may have difficulty continuing, especially those with tetraplegia and complete injuries. Females also have more difficulty than males in maintaining compliance with IC procedures.

  • Intermittent catheterization, whether performed acutely or chronically, has the lowest complication rate.

    Indwelling catheterization, whether suprapubic or urethral or whether conducted acutely or chronically, may result in a higher long-term rate of urological and renal complications than other management methods.

    Persons with tetraplegia and complete injuries, and to a lesser degree females, may have difficulty in maintaining compliance with intermittent catheterization procedures following discharge from rehabilitation.

Intermittent Catheterization

Intermittent catheterization is the preferred method of bladder management likely due to a reduced incidence of renal impairment, reflux, stone disease, bladder cancer and possibly UTI compared to other methods of bladder management (Groah et al. 2002; Weld & Dmochowski 2000; Ord et al. 2003). The present section outlines those studies focusing on specific aspects of intermittent catheterization, including timing of catheterization and catheter selection, (Polliack et al. 2005; Waller et al. 1997; De Ridder et al. 2005; Giannantoni et al. 2001; Kovindha et al. 2004; Sarica et al. 2010). Effectiveness of intermittent catheterization in emptying the bladder is addressed in Jensen et al. (1995). Long-term follow-up data of patients managed by intermittent catheterization is provided in the articles by Ku et al. (2006), Perrouin-verbe et al. (1995) and Nanninga et al. (1982).

Table: Intermittent Catheterization

Discussion

Intermittent catheterization (IC) is the mode of bladder management generally associated with the fewest long-term complications (Groah et al. 2002; Weld & Dmochowski 2000; Ord et al. 2003).  However, there are some complications that occur with higher frequency in patients who intermittently catheterize.  For example, increased urethral complications (19% incidence) may lead to urosepsis and epididymorchitis (28.5% incidence) and may result in increased morbidity and reduced fertility (Ku et al. 2006).  Despite these IC related higher rates of complications, there is good consensus among the larger retrospective studies available that intermittent catheterization programs are still preferred for the protection of the upper urinary tract through regular emptying with low bladder pressures (Giannantoni et al. 2001).  Episodes of pylonephritis and UTI are also reduced when bladder emptying is conducted consistently and completely in the absence of indwelling catheters (Groah et al. 2002; Weld & Dmochowski 2000; Ord et al. 2003; Giannantoni et al. 2001). Perrouin-Verbe et al. (1995) showed that patients most likely to continue with intermittent catheterization would be those who are able to independently catheterize and those who have an acceptable level of continence. In line with this finding, Pannek & Kullik (2009) showed that in patients who employ self IC and have optimal bladder function, perceived quality of life is higher than those with suboptimal function.  Thus it is essential to consider an individual’s activities of daily living, psychological factors (and other concurrent comorbidities) and potential caregiving needs when intermittent catheterization is being introduced early after SCI.

A very low incidence of bladder stones and hydronephrosis were reported in Perouin-Verbe et al. (1995) (2%), consistent with previously discussed studies. However, Nanninga et al. (1982), reported upper tract changes in 33% of patients. While this range is large, it is possible that management of patients in 1982 involved less stringent control of high bladder pressures which is the cause of upper tract disease in many cases (Nanninga et al. 1982). Nanninga noted that high bladder pressures may occur even in patients who remain continent or nearly continent between catheterizations, and that the problem can at least be partially avoided by increasing the frequency of catheterization. Other options for patients with persistently elevated pressures already on intermittent catheterization programs are detrusor Botox injections and/or anticholinergic medications.  It is important to note that regular follow-up of these patients including tests of bladder physiology and upper tract function is recommended to monitor for changes and for increasing incidence of complications with time (Perrouin-Verb et al. 1995; Nanninga et al. 1982). 

There are several trials investigating varying properties of catheters used for IC (De Ridder et al. 2005; Giannantoni et al. 2001; Waller et al. 1997; Sarica et al. 2010). For example, Giannantoni et al. (2001) demonstrated a reduction in the incidence of UTIs and in the presence of asymptomatic bacteriuria for a pre-lubricated catheter versus a conventional PVC catheter. Of note are 3 subjects initially requiring assistance with a conventional catheter transitioning to independence with a pre-lubricated catheter. However, the order of cather use by type was not reported. In terms of general satisfaction, subjects rated the pre-lubricated catheter significantly higher than the conventional catheter with respect to comfort, ease of insertion, extraction, and handling. Reduced incidence of UTIs was reported by De Ridder et al. (2005) in favour of hydrophilic catheters when compared to conventional PVC catheters. Although this multi-centre investigation employed a RCT design (N=123) results should be cautiously interpreted given a 54% drop-out rate. A third investigation examining catheter properties investigated the effect of osmolality on two different hydrophilic catheters. Waller et al. (1997) demonstrated reduced friction with the high-osmality catheter vs the other, a finding corroborated by nursing reports of fewer catheter “stickings”. These differences did not translate into clinically significant results for differences in the incidence of UTIs with either hydrophilic catheter type. Sarica et al. (2010) found gel lubricated non-hydrophilic cathethers to be superior to hydrophilic coated and PVC catheters in terms of reduced urethral microtrauma and pyuria, and increased patient satisfaction, despite higher cost. Finally, a study by Kovindha et al. (2004), provides data on a reusable (average of 3 years of usage) silicone catheter. The frequency of UTIs reported for the reuseable catheter is comparable to that reported for standard disposable catheters (3-7 days of usage), but inferior to frequencies reported for prelubricated catheters. Kovindha et al. (2004) stated that the long-term silicone catheter is an economical option for those in developing countries. In developing countries, the high cost of the single use, prelubricated catheters is prohibitive outside of exceptional situations.

It should be noted that some assistive devices that may enhance compliance with intermittent catheterization for those with impaired hand function do exist, but are likely not in widespread use. For example, Adler and Kirshblum (2003) reported a series of 9 individuals with C5-C7 SCI, originally unable to perform intermittent catheterization, that were subsequently satisfied and successful with a device to help performance of intermittent catheterization.  

Conclusion

  • There is Level 1 evidence based on 1 RCT that pre-lubricated hydrophilic catheters are associated with fewer UTIs and reduced incidence of urethral bleeding and microtrauma as compared to conventional Poly Vinyl Chloride catheters.
  • There is Level 2 evidence based on 1 lower quality RCT that fewer UTIs, but not necessarily urethral bleeding may result with the use of hydrophilic catheters as compared to conventional PVC catheters.
  • There is Level 2 evidence based on 1 lower quality RCT that urethral microtrauma and pyuria is reduced with use of gel-lubricated non-hydrophilic catheter, with higher patient satisfaction, as compared to hydrophilic-coated or PVC catheters
  • There is level 4 evidence that urethral complications and epididymoorchitis occurs more frequently in those using IC programs for bladder emptying, but the advantages of improved upper tract outcome over those with indwelling catheters outweigh these disadvantages.
  • There is level 4 evidence that using a portable ultrasound device reduces the frequency and cost of intermittent catheterizations. 
  • Although both pre-lubricated and hydrophilic catheters have been associated with reduced incidence of UTIs as compared to conventional Poly Vinyl Chloride catheters, less urethral microtrauma with their use may only be seen with pre-lubricated catheters.

    Urethral complications and epididymoorchitis occur more frequently in those using intermittent catheterization programs.

    Portable ultrasound device can improve the scheduling of intermittent catheterizations.

Triggering-Type or Expression Voiding Methods of Bladder Management

Individuals with SCI undergoing inpatient rehabilitation are sometimes taught various maneuvers in order to initiate or attempt spontaneous voiding, termed “expression voiding” as well as to provide a “trigger” to initiate voiding (Wyndaele et al. 2001). As noted previously, these involve methods to increase intra-abdominal pressure so as to facilitate voiding. Only 1 study examining these methods met the criteria for inclusion in the present review.

Table: Triggering-Type or Expression Voiding Methods

Discussion

Greenstein et al. (1992) documented the use of Valsalva and Crede maneuvers to initiate spontaneous voiding in a small case series of 5 males with paraplegia. In his review, Wyndaele et al. (2001) states that bladder “voiding” by this method utilizes C-fibre activation,  to trigger the sacral reflex resulting in involuntary and non-sustained bladder contraction. Wyndaele et al. (2001) cautions readers that DESD may occur in a high percentage of patients who can activate bladder emptying in this manner, resulting in the potential for upper tract changes, as well as incomplete emptying. Greenstein et al. intended to examine the potential for long-term complications in those who employed these techniques over an extended period of time. High intravesical pressure was documented during voiding. The authors suggested that long-term monitoring for these individuals is advisable and intermittent catheterization should replace these methods in the event of urological complications. Triggered voiding and use of the crede maneuver to initiate “voiding” should only be considered in patients with normal upper tracts, provided that urodynamic studies demonstrate low pressure storage and “voiding”, and that there is a low incidence of UTI.

Conclusion

There is level 4 evidence that triggering mechanisms such as the Valsalva or Crede maneuvers may assist some individuals with neurogenic bladder in emptying their bladders without catheterization. However, high intra-vesical voiding pressures can occur which could conceivably lead to renal complications.

  • Valsalva or Crede maneuver may assist some individuals to void spontaneously but produce high intra-vesical pressure, increasing the risk for long-term complications.

Indwelling Catheterization (Indwelling or Suprapubic)

Urethral catheterization may be the bladder management method of choice for a variety of reasons including the following: ease of management, inadequate hand function for Intermediate catherizations, severe spasticity, low bladder capacity with high detrusor pressures and/or persistent incontinence especially in women, and pressure ulcers (Yavuzer et al. 2000). Suprapubic catheterization, first described in SCI by Cook and Smith (1976), is the preferred choice for those patients who require an indwelling catheter but have severe urethral disease. Weld and Dmochowski (2000) presented data showing a lower overall complication rate from suprapubic catheter use than from urethral catheter use (44.4% vs 53% respectively). Since indwelling catheterization is sometimes unavoidable, becoming familiar with the various potential complications and appropriate monitoring is important for clinical and self-management of neurogenic bladder.

Based on a series of case review studies (most described earlier in Section 13.4.3.1) comparing various bladder management methods, long-term use of indwelling catheters is associated with generally higher rates of complications (Wyndaele et al. 1985; Gallien et al. 1998; Weld & Dmochowski 2000) in contrast to other methods (especially Intermeiadite catherizations). For example, Ord et al. (2003) noted a significantly greater chance of having bladder stones with long-term suprapubic catheter or urethral indwelling catheter use as indicated by hazard ratios of 10.5 and 12.8 relative to intermittent catheterization respectively. Indwelling catheterization has also been linked to significantly higher rates of bladder cancer development (Groah et al. 2002; Kaufman et al. 1977) and upper tract deterioration (Weld & Dmochowski 2000) as compared to those who use long-term intermittent catheterization.

Table: Indwelling Catheterization

Discussion

Although Intermediate catherizations are the first choice for neurogenic bladder management, some patients with subacute SCI are managed with indwelling catheters due to prolonged high urine output states, frequent intercurrent medical illnesses or surgical complications, or severe incontinence. Suprapubic catheterization is occasionally considered during this early period if urethral damage has occurredas a result of prolonged urethral catheter use. Later, in chronic situations, suprapubic catheterization may also be favored by individuals with SCI who are obese, have severe lower extremity spasticity, inadequate hand function, persistent incontinence, urethral stricture or erosion, or because of perceived increased ability to engage in sexual relations (Weld & Dmochowski 2000; Peatfield et al.1983). Prostatitis and orchiepidymitis occur less frequently in those with suprapubic catheterization but upper tract deterioration remains a concern (Gallien et al. 1998; Weld & Dmochowski 2000; Sugimura et al. 2008).

Hackler (1982) has suggested that upper tract deterioration may be reduced with concomitant use of anticholinergic medication. MacDiarmid et al. (1995) hypothesized that clinical factors may also reduce the complication rate. They attributed the low incidence of complications during the year-long data collection period to strict adherence to a catheter protocol with regular follow-up and close surveillance utilizing a dedicated medical and nursing team and informed primary care practitioners. Sugimura et al. (2008) also noted that upper tract complication rates resulting from suprapubic catheterization may be lower than earlier studies suggested and reported a 13.4% renal complication rate associated with a mean follow-up period of 68 months. Furthermore, Sherriff et al. (1998) conducted a satisfaction survey regarding suprapubic catheter use which indicated 70-90% satisfaction based on questions such as impact on life, pleasure with the switch, and “would you do it again”, etc.

Several of the studies described above on suprapubic catheterization contain a relatively short follow-up period (e.g., < 10 years). The specific concerns regarding indwelling catheter use centre on the potential for urological complications with long-term use. Many patients are injured as young adults, and may live for greater than 50 years and therefore the target for safety monitoring regarding bladder management choice should emulate SCI life expectancy. According to the prospective study by Kaufman et al. (1977), the risk of bladder cancer with indwelling urethral catheters increase significantly with duration of use. Interestingly, his data suggest that routine screening with bladder biopsy may be indicated in addition to cystoscopy for those at highest risk of bladder cancer. Research since this time suggests, however, that there is no good evidence for screening cystoscopy in this population; the requirements of a test to be a good screening tool have not met (Yang et al., 1999). Kaufman et al. (1977) did not include a significant number of suprapubic catheter users, but Groah et al. (2002) did include both types of indwelling catheter users, and clearly showed a higher incidence of bladder cancer in such patients compared to those not managing their bladders with indwelling catheters. Stone disease, upper tract deterioration, reflux, and chronic infection remain additional long term concerns in those who resort to indwelling catheter use, with a slightly lower overall incidence reported in those with suprapubic vs. urethral catheters (Weld & Dmochowski 2000).

Conclusion

  • There is level 4 evidence, despite an associated significant incidence of urological and renal complications, acute and chronic indwelling suprapubic catheterization may still be a reasonable choice for bladder management for people with poor hand function, lack of care-giver assistance, severe lower limb spasticity, urethral disease, and persistent incontinence with urethral catheterization.
  • There is level 4 evidence that those with indwelling catheters are at higher risk for bladder cancer compared to those with non-indwelling catheter management programs. Screening for cancer may require routine biopsy as well as cytoscopy.
  • With diligent care and ongoing medical follow-up, indwelling suprapubic catheterization may be an effective and satisfactory bladder management choice for some people, though there is insufficient evidence to report lifelong safety of such a regime.

    Indwelling catheter users are at higher risk of bladder cancer, especially in the second decade of use, though risk also increases during the first decade of use.

Condom Catheterization

A viable option for bladder management in males is condom catheterization. As noted above, condom catheterization is associated with relatively fewer complications than indwelling methods but more complications than intermediate catherization (Ord et al. 2003; Hackler 1982). However, complications may still arise, as described by Newman & Price 1985). Of greatest concern is incomplete drainage, which may lead by persistently high bladder pressures, recurrent UTIs and the likelihood of glomerular filtration rate deterioration described below. Sometimes this situation necessitates adjuvant daily or twice daily catheterization, medications, or sphincterotomy. Medications to improve drainage, such as alpha blockers can improve emptying by reducing outlet resistance, and sometimes by reducing pressures. Newman & Price (1985) raise practical issues such as cleanliness and proper use of appliances. Application difficulties with condom catheterization are likely problematic in the event of impaired hand function. Slippage of the condom can result in leaks. Perkash et al. (1992) describe the use of penile implants, in part as a means to circumvent this issue with condom application. 

Table: Condom Catheterization

Discussion

Bladder management through condom drainage is often chosen to oversome persistent incontinence that may occur with other methods of bladder management. However, periodic monitoring for bladder “residuals” and complete emptying, as emphasized by Newman and Price (1985) following a review of 60 SCI patients with external catheters. Elevated residuals should raise the possibility of excessive bladder pressure resultsing from incomplete emptying ads a spastic sphincter. This is a situation that can easily be assessed by urodynamic studies. Though Newman and Price (1985) indicated a high prevalence of bladder trabeculation, and implied that this occurred secondary to high pressure, no corroborating urodynamic data was provided. Sphincterotomy is a surgical procedure that eliminates outlet resistance and one that almost 30% of the study group in Newman and Price (1985) had undergone. Another problem commonly described with condom drainage is infection. It is difficult to make conclusions in this area based on the rather generalized description of a positive culture (“any organism growing”) as presented by Newman and Price (1985).

Some patients prefer condom drainage for convenience, as there is usually no need or reduced need to catheterize, compared to regimes that involve sole use of clean intermittent catheterization. However, this convenience can be offset by accidental leaks, and skin problems at the site of condom attachment. Perkash et al. (1992) conducted a retrospective analysis of 79 male patients with penile implants in place over a mean time of 7.08 years. A primary reason for obtaining a penile implant in these patients, among others, was to provide a stable penile shaft to hold a condom for external urinary drainage. In addition, penile implantation allowed some to switch to a more effective and safer bladder management method (i.e. 18% no longer required an indwelling catheter). All patients reported improved continence as reflected in the general observation that it was easier to keep themselves clean and dry.

Conclusion

  • There is level 4 evidence that condom drainage may be associated with urinary tract infection and upper tract deterioration.
  • There is level 4 evidence that penile implants may allow easier use of condom catheters, thereby reducing incontinence and improving sexual function.
  • Patients using condom drainage should be monitored for complete emptying and for low pressure drainage, to reduce UTI and upper tract deterioration. Sphincterotomy may eventually be required.

    Penile implants may allow easier use of condom catheters and reduce incontinence.

Continent Catheterizable Stoma and Incontinent Urinary Diversion

People with tetraplegia, especially females often have difficulty performing clean intermittent catherization. In addition, females are more troubled by persistent incontinence. The surgical methods described in this section can result in the ability to self-catheterize, allowing the individual to benefit from intermittent rather than indwelling bladder catheterization, the latter being associated with a higher rate of complications. The mitrofanoff channel involves the use of an autologous tubular structure, usually the appendix, as a cutaneous catheterizable stoma. Implantation in the bladder via a submucosal tunnel provides continence to the conduit (Sylora et al. 1997). The stoma can be hidden in the umbilicus. While performed often in children, the procedure has less commonly been performed in adults. Long term followup is unknown, particularly with respect to the potential for malignancies. Karsenty et al. (2008) describes a similar procedure, performed in 13 patients with incontinence and inability to self-catheterize.

Ileal conduit diversion, another surgical approach more commonly performed in females, is also often considered for reasons of lack of manual dexterity or ease of care and convenience (Pazooki et al. 2006; Chartier-Kastler et al. 2002). This technique aims to establish low-pressure urinary drainage by diverting urine prior to entering the bladder and connecting the ureters to an external urinary collection system via a catheter passed through the ileal lumen. This procedure is sometimes conducted along with removal of the bladder as well (Chartier-Kastler et al. 2002; Kato et al. 2002).

Table: Continent Catheterizable Stoma and Incontinent Urinary Diversion

Discussion

Continent Catheterizable Stoma

Despite small sample sizes, the results of the above studies are very promising. High levels of continence, independence, and the ability to manage the bladder with intermittent catheterization are reported in all three studies. The stability of serum creatinine has implications for upper tract function (Karsenty et al. 2008). Hakenberg et al. (2001) reported safe urodynamic bladder storage pressures (20-44 mm H20) on patients that underwent appendicovesicostomy with cutaneous stoma. Participants in this study and the study by Sylora et al. (1997) were kept on anticholinergic medication, a consideration that ensures low pressure storage in those with persistent hyperreflexia and dyssynergia, and contributes to ongoing continence. Complications occur, most concerning of which are those requiring surgical procedures (pelvic abscess, bowel occlusion, stomal revision for stenosis). Larger sample sizes would be necessary to determine true incidence. Length of follow-up ranged from 20 – 44 months, which does not provide sufficiently long term safety and effectiveness data. However, given the importance of the clinical achievements (i.e., independent use of intermittent catheterization; continence) further study with larger sample sizes is warranted.

Incontinent Urinary Diversion

Ileal conduit diversion is another surgical procedure noted with some frequency in the literature. Chartier-Kastler et al. (2002) and Kato et al. (2002) have reported separate case series (N=33 and N=16 respectively) examining this approach. Chartier-Kastler et al. (2002) reported all patients became continent after initially being incontinent prior to surgery and Kato et al. (2002) reported that most patients were more satisfied with the procedure than their previous management method upon survey a few months after the operation. Both authors also reported several long-term complications (e.g., pyocystitis, suprapubic collection – genital secretions), chronic urethral leakage, acute pyelonephritis). However, it is uncertain if these high complication rates would be comparable in the event individuals had continued with their previous form of bladder management, as often surgical procedures are performed only if other more conservative methods are unsuccessful. Controlled trials (e.g., case control study design) would be beneficial to address this issue.

Colli & Lloyd (2011) evaluated a series of cases (N=35) involving bladder neck closure (BNC) which was paired with permanent suprapubic catheter (SPC) diversion as opposed to other forms of urinary diversion, such as ileovesicotomy or continent catheterizable stoma. Their results suggest that BNC in conjunction with SPC diversion offers urethral continence with a reasonable complication rate (17%). A straightforward operative approach without violation of the peritoneum, no need for enteric reconstruction, and possible reduction of bowel complications are additional advantages conferred by this technique. Specific disadvantages, such as a reduced likelihood of success in very low bladder capacity patients were noted.

Conclusion

  • There is level 4 evidence that most individuals who receive catheterizable stomas become newly continent and can self-catheterize. It appears possible that this surgical intervention could protect upper tract function. Larger studies are needed to better evaluate true incidence of complications, and long-term bladder and renal outcome.
  • There is level 4 evidence that most individuals undergoing cutaneous ileal conduit (ileo-ureterostomy) diversion became newly continent and were more satisfied than with their previous bladder management method. Long-term follow-up demonstrated the presence of a high incidence of urological or renal complications. 
  • Catheterizable abdominal stomas may increase the likelihood of achieving continence and independence in self-catherization, and may result in a bladder management program that offers more optimal upper tract protection.

    Cutaneous ileal conduit diversion may increase the likelihood of achieving continence but may also be associated with a high incidence of various long-term complications.

Electrical Stimulation for Bladder Emptying (and Enhancing Volumes)

Although electrostimulation to enhance bladder volume and induce voiding has been studied since the 1950’s it was not until the development of the Brindley anterior sacral nerve root stimulator, and subsequent implantation of the first device in a human in 1978 that widespread clinical applications have been available (Egon et al. 1998; Brindley et al. 1982). Others have noted the important role of Tanagho and Schmidt (1982) in developing this approach – also termed sacral neuromodulation – by conducting a series of experiments to elucidate the neuroanatomical basis of electrical stimulation in enhancing bladder function (Hassouna et al. 2003). Although there are several configurations,[1] Creasey et al. (2001) described the system employed in most investigations (i.e., the Finetech-Brindley system), as consisting of an implanted internal stimulator-receiver which is controlled and powered via telemetered radio transmission by an external controller-transmitter. Cables and electrodes are also implanted which are held in contact with sacral nerves (i.e., often S2-S4). This system allows programmable stimulation patterns and permits control of both bowel and bladder function. Often dorsal sacral rhizotomy is performed at the same time as stimulator implantation (Vastenholt et al. 2003; Creasey et al. 2001; Egon et al. 1998; Martens et al. 2011).

Various investigators have examined other forms of stimulation including direct bladder stimulation (Madersbacher et al. 1982; Radziszweski et al. 2009) or employing stimulators intended for other purposes such as enhancing muscle functions for improving movement, spasticity or muscle strength (Katz et al. 1991; Wheeler et al. 1986). In addition, multi-functional stimulators may be configured to provide similar stimulation patterns to similar targets as the bladder-specific stimulators. As noted previously (Section 13.3.2.1 Electrical Stimulation to Enhance Bladder Volumes), the present section describes studies that assess outcomes associated with both bladder emptying and bladder storage as appropriately configured stimulation may result in improvements in both of these functions.

Table: Electrical Stimulation to Trigger Bladder Emptying and Enhance Bladder Volume

Discussion

Sacral neuromodulation or sacral anterior root stimulation combined with sacral deafferentation is the most well studied method of triggering bladder emptying via electrical stimulation techniques with many investigators incorporating retrospective case series or prospective pre-post study designs comprising level 4 evidence (Robinson et al. 1988; Van Kerrebroeck et al. 1996; Van Kerrebroeck et al. 1997[1]; Egon et al. 1998; Creasey et al. 2001; Vastenholt et al. 2003; Kutzenberger et al. 2005; Kutzenberger 2007; Lombardi & Del Popolo 2009; Possover 2009). Typical participant characteristics for these studies include: detrusor overactivity; incomplete bladder emptying and frequently recurrent UTI; incontinence; and vesicoureteric reflux, refractory to conservative treatment. In each of these studies, a large percentage of subjects did become continent and were able to successfully void with these devices, whereas this was typically not the case for most participants with whatever bladder management method was used prior to implantation. These findings appear to persist in that several reports have noted continued improvement with successful continence rates of 73-88% over an average follow-up period up to 8.6 years (Egon et al. 1998; Vastenholt et al. 2003; Kutzenbergen et al. 2005; Kutzenberger 2007; Lombardi & Del Popolo 2009). Of note, Lombardi and Del Popolo (2009) conducted a study that included patients with underactive bladder (n=13) in addition to those with overactive bladder (n=11) and reported similar results for both groups (i.e., reduction in incontinence and increased voiding volume). However, 30.8% of persons in the underactive bladder group had a loss of efficacy over the follow-up period (mean of 60.7 months) as compared to none in the overactive bladder group.

Several of these investigators reported a significant decrease in UTIs (Van Kerrebroeck et al. 1996; Egon et al. 1998; Vastenholt et al., 2003; Creasey et al. 2001; Kutzenberger et al. 2005; Kutzenberger 2007; Martens et al. 2011) and autonomic dysreflexia (Van Kerrebroeck et al. 1996; Egon et al. 1998; Creasey et al. 2001; Kutzenberger et al. 2005; Kutzenberger 2007; Possover 2009) among participants, even after long-term use. Some investigators performed satisfaction surveys and reported that most participants remained satisfied with the device, even after many years. In particular, Vastenholt et al. (2003) and Martens et al. (2011) conducted a Qualiveen questionnaire for assessing the bladder health-related quality of life and impact of urinary problems. In the Vastenholt et al. (2003) study, the top 3 advantages noted by stimulator users was a reduction in UTIs (68% reporting), improved social life (54%) and improved continence (54%). Martens et al. (2011) reported improved quality of life scores (Qualiveen and SF-36), a significantly better Specific Impact of Urinary Problems score and continence rate, in addition to reduced UTIs for patients undergoing a Brindley procedure.

Posterior rhizotomy was performed in addition to implantation of a sacral root stimulator in most reports (Creasey et al. 2001; Van Kerrebroeck et al. 1996; Egon et al. 1998; Kutzenberger et al. 2005; Kutzenberger 2007; Martens et al. 2011). The stated benefit of this deafferentation is the abolition of dyssynergia and high intravesical pressures, reduced risk of hydronephrosis and reflex incontinence. The cost is the loss of bowel reflexes and reflex erections. Nonetheless, most authors report improved bowel management in many of their patients (since the stimulator is activated during the bowel routine), and a great improvement in autonomic dysreflexia (Van Kerrebroeck et al. 1996; Egon et al. 1998; Creasey et al. 2001; Kutzenberger 2007). In Robinson et al. (1988) sphincterotomies were performed on 3 patients with persistent reflex incontinence, and/or upper tract deterioration, while 3 patients were given sphincterotomies pre-implantation to prevent anticipated autonomic dysreflexia. Thus, sphincterotomy has shown some success as an option for producing some of the benefits attributed to posterior rhizotomy.

A primary purpose of posterior rhizotomy is the attainment of an areflexic bladder, thus allowing a more compliant reservoir with the potential for greater bladder capacity under lower pressure. Results from all investigations measuring capacity have shown this to be true with significant increases in bladder capacity at lower pressures associated with combined sacral anterior root stimulation and sacral deafferentation (Creasey et al. 2001; Van Kerrebroeck et al. 1996; Egon et al. 1998; Kutzenberger et al. 2005, 2007). Several investigations have been conducted using different approaches aimed at conditioning the bladder with different forms of stimulation so as to achieve the same effect of increasing bladder capacity under low-pressure conditions in persons with SCI with overactive bladder and intact dorsal sacral nerves (Madersbacher et al. 1982; Kirkham et al. 2002; Kirkham et al. 2002; Bycroft et al. 2004; Hansen et al. 2005). Additionally, rhizotomy alone (without a stimulator) has shown to result in higher quality of life scores over matched controls (Martens et al. 2011).

Of note, Kirkham et al. (2002) implanted the same sacral anterior root stimulator used in the majority of investigations (i.e., Finetech-Brindley stimulator) in a small group of patients (n=5) without posterior rhizotomies and therefore configured the stimulator to deliver both anterior and posterior sacral root stimulation. The conditioning posterior root stimulation was effective in producing increased bladder capacity in 3 of 5 subjects and the anterior root stimulation was able to elicit bladder emptying, but with significant residual volumes. (Note: the 2 remaining subjects sustained posterior root damage and were not included in post-operative testing.) This preliminary trial suggests there is a possibility of achieving success with sacral anterior root stimulation without necessitating the destructive posterior root ablation.

Others have conducted more mechanistic investigations of conditioning stimuli delivered to the pudenal, dorsal penile or clitoral nerve (Spinelli et al 2005; Kirkham et al. 2001) or magnetic stimulation applied over the sacral nerves (Bycroft et al. 2004) and achieved demonstrations of detrusor inhibition or increased bladder capacity under lower pressure. Further developmental work would be required before these or modified approaches could be incorporated clinically as an approach that permits bladder stimulation in the absence of deafferentation.

Recently, Possover (2009) reported a new surgical technique applied to persons with SCI involving laparoscopic transperitoneal implantation of neural electrodes to pelveoabdominal nerves, which they have termed the ‘‘LION procedure’’ (i.e., laparoscopic implantation of neuroprosthesis). With this method, which is far less invasive than the traditional dorsal approach for stimulator implantation, the risk associated with immediate or long-term complications (e.g., meningitis, encephalitis, infections) is significantly reduced. In addition, the destructive procedures of rhizotomy and laminectomy are not necessary. Possover (2009) conducted this procedure on a series of 8 persons previously having an explanted Brindley-Finetech stimulator, 6 of whom had viable sacral nerves. This resulted in adequate detrusor contractions enabling complete bladder emptying still present at follow-up (3-27 months). Patients undergoing this procedure returned home after only a 3-5 day hospital stay and there were no reported complications.

Another approach has been to apply stimulation to the bladder itself, most appropriately done during initial rehabilitation (Madersbacher et al. 1982; Radziszweski et al. 2009). Radziszweski et al. (2009) applied daily 15 minute bouts of transcutaneous electrical stimulation directly to the bladder for 30 days in patients seen by the Rehabilitation Department of a Military Hospital (time since injury not reported). These authors demonstrated significant increases in bladder capacity and peak flow velocity and a significant decrease in residual urine volume immediately following stimulation and persisting at 2 months follow-up compared to baseline. A similar approach was reported by Madersbacher et al. (1982) in which stimulation, in the form of impulse packages applied to a saline filled bladder, was administered over a variable treatment period after which the treatment effect persisted up to one year when most subjects reported a definite waning of the benefits. Unlike other studies involving sacral neuromodulation, this was conducted on those more recently injured with 17 of 29 becoming continent and 10 others becoming socially dry without need for pads and urinals. This study involved a case series design but would have been much more powerful with the inclusion of a control group, given the potential for natural bladder recovery in individuals with more recent injuries. Further research would also be needed to examine safety information related to bladder pressure during voiding, and follow-up of any potential renal changes before considering this intervention.

Sievert et al. (2010) also capitalized on the concept of neural plasticity through early (upon confirmation of bladder acontractility) sacral neromodulation (SNM) and reported no instances of detrusor overactivity and urinary incontinence with normal bladder capacity, reduced UTI rates and improved bowel and erectile functionality without nerve damage. Although follow-up was reported for greater than 2 years, further investigations are needed to augment the small sample size (nSNM=10) and involve fMRI to confirm plastic changes within the brain of those patients undergoing SNM vs those pharmacologically treated.

Other investigators have examined the effects on the urinary system associated with stimulation directed towards other targets For example, Katz et al. (1991) tested the effect of epidural dorsal spinal cord stimulation, intended primarily for spasticity relief, at T1 (for those with tetraplegia) or T11-T12 (for those with paraplegia). Wheeler et al. (1986) investigated the effect of 4 to 8 weeks of quadriceps muscle reconditioning by surface electrical stimulation (FES) bilaterally, intended primarily for strength and spasticity. In each case, these techniques had marginal effects on bladder function. However, in the latter experiment it was noted that some subjects did achieve beneficial changes in bladder function and that these tended to be most noticeable in the same subjects that showed positive improvements in strength and spasticity.

Conclusion

  • There is level 4 evidence from eight studies and level 5 evidence from a single study that ongoing use of sacral anterior root stimulation (accompanied in most cases by posterior sacral rhizotomy) is an effective method of bladder emptying resulting in reduced incontinence for the majority of those implanted. This is associated with increased bladder capacity and reduced post-void residual volume.
  • There is level 4 evidence from five studies and level 5 evidence from a single study (UTIs only) that sacral anterior root stimulation (accompanied in most cases by posterior sacral rhizotomy) may be associated with reducing UTIs and autonomic dysreflexia.
  • There is level 4 evidence from two studies that direct bladder stimulation may result in reduced incontinence, increased bladder capacity and reduced residual volumes but requires further study as to its potential clinical use.
  • There is level 4 evidence from various single studies that other forms of neuroanatomically-related stimulation (e.g., electrical conditioning stimulation to posterior sacral, pudenal, dorsal penile or clitoral nerve or surface magnetic sacral stimulation) may result in increased bladder capacity but require further study as to their potential clinical use. Further development involving some of these approaches may permit sacral anterior root stimulation without the need for posterior root ablation.
  • There is limited level 2 evidence from a single small study that reports early sacral neuromodulation may improve management of lower urinary tract dysfunction. Further investigation is required to confirm the results and substantiate the hypothesis of resultant plastic changes of the brain.
  • There is level 4 evidence from a single study that epidural dorsal spinal cord stimulation at T1 or T11 originally intended for reducing muscle spasticity may have little effect on bladder function.
  • There is level 4 evidence from a single study that a program of functional electrical stimulation exercise involving the quadriceps muscle originally intended for enhancing muscle function and reducing muscle spasticity has only marginal (if any) effects on bladder function.
  • Sacral anterior root stimulation (accompanied in most cases by posterior sacral rhizotomy) enhances bladder function and is an effective bladder management technique though the program (surgery and followup) requires significant expertise.

    Direct bladder stimulation may be effective in reducing incontinence and increasing bladder capacity but requires further study.

    Posterior sacral, pudenal,dorsal penile or clitoral nerve stimulation may be effective to increase bladder capacity but requires further study.

    Early sacral neural modulation may improve management of lower urinary tract dysfunction but requires further study.

Sphincterotomy, Artificial Sphincters, Stents and Related Approaches for Bladder Emptying

Transtherurethral sphincterotomy and related procedures such as insertion of artificial sphincters, sphincteric stents or balloon dilation of the external urinary sphincter provide a means to overcome persistent dysynergia (Chancellor et al. 1999; Juma et al. 1995; Chancellor et al. 1993a; Chancellor et al. 1993b; Patki et al. 2006; Seoane-Rodriguez et al. 2007). Often these are performed when intermittent catheterization is not an option because of lack of manual dexterity and when more conservative options have proven unsuccessful (Chancellor et al. 1999; Juma et al. 1995).

Table: Sphincterotomy, Intraurethral Stent Insertion and Related Approaches for Bladder Emptying

Discussion

A common surgical method of treating bladder outlet obstruction or detrusor-sphincter dyssynergia has been transurethral sphincterotomy usually done in anticipation of emptying the bladder with condom drainage with reflex “voiding”. Autonomic dysreflexia (AD), a common complication of high volume storage and/or high pressure “voiding” or leaking in SCI patients with spinal lesions typically above T12, can be diagnosed with blood pressure (BP) monitoring during cystometrogram and urodynamic studies and subsequently better managed after successful transurethral sphincterotomy (Perkash 2007). Perkash (2007) noted a highly significant (p<0.0001) decrease in systolic and diastolic BP after transurethral sphincterotomy as well as improved voiding and post-void residuals. However, although diminished symptoms of AD were reported, mean maximum voiding pressures changes were not significant.

Juma et al. (1995) reported a case series of 63 individuals who had received 1 or more sphincterotomies with a mean follow-up time of 11 (range 2-30) years. This study was directed at describing the risk for long-term complications following this procedure. Although more than half of these individuals had normal upper tract imaging studies a significant proportion had complications - with 25/63 having some upper tract pathology (i.e., 12 renal calculi, 11 renal scarring, 1 atrophic kidney, 1 renal cyst). Nineteen of these were deemed significant. Risk of significant upper tract complications in presence or absence of bacteria was 38% and 13% respectively. Thirty out of 63 had lower tract complications (5 bladder calculi, 10 recurrent UTI, 3 urethral diverticula, 6 urethral stricture or bladder neck stenosis and 6 recurrent epididymitis). These authors noted that the most reliable urodynamic measure for predicting potential complications following sphincterotomy appeared to be an increase in leak point pressure. Complication rates of 50% were noted for those with leak point pressure of > 70 cm H2O, whereas rates were reduced to 25% when leak point pressure was < 30 cm H2O.

Despite possible upper renal tract protection and extended periods of satisfactory bladder function (i.e., 81 months), long-term outcome data (Pan et al. 2009) caution that high rates of recurring bladder dysfunction symptoms (68%) require approaching sphincterotomy as a staged intervention given that 36% (30/84) of patients required a second procedure to achieve the mean extended period of satisfactory bladder function. When considering these studies, it is uncertain if these high complication rates would be comparable in the event individuals had continued with their previous form of bladder management as often surgical procedures are performed only if other more conservative methods are unsuccessful. A controlled trial is required to address this issue. For cases where DESD is paired with with bladder neck dyssynergia (which should be confirmed with videourodynamic study), Ke & Kuo (2010) have shown that transurethral incision of the bladder neck (TUI-BN) may restore contractility of the detrusor. PVR decreased and QMax increased significantly after TUI-BN and an open urethral sphincter was noted in 19 of 22 patients studied postoperatively. In addition, autonomic dysreflexia during micturition was also reduced or eliminated in 15 of the 17 patients with AD preoperatively (Ke & Kuo 2010).

One alternative to sphinterotomy is placement of a stent passing through the external sphincter thereby ensuring an open passage. Several studies have been conducted examining the long-term outcomes associated with different types of stents including a wire mesh stent (UroLume) (Chancellor et al.1993a, Abdill et al. 1994, Chancellor et al. 1995; Abdul-Rahman et al. 2010) and a nickel-titanium alloy tightly coiled stent (Memokath) (Mehta & Tophill 2006). Long-term outcomes of each of these stents were also investigated in a retrospective case series study of 47 consecutive male patients (Seoane-Rodriguez et al. 2007). All of these studies involved either retrospective case series reviews or prospective pre-post study designs and demonstrated effective treatment of incontinence initially while the stent was in place although some studies also showed the necessity for stent removal due to migration or other complications. In particular, Mehta and Tophill (2006), in a case series of 29 persons with SCI with a follow-up of up to 47 months suggested that the “working life” of the Memokath stent was 21 months. They noted that complications most commonly leading to removal included stent blockage by encrustation, migration (especially in single-ended models), UTIs and persistent haematuria. Others have noted similar issues but typically have reported lower rates of complications leading to stent removal (Abdill et al. 1994, Chancellor et al. 1995, Seoane-Rodriguez et al. 2007; Abdul-Rahman et al. 2010). Despite these issues, when the stents are in place they appear to be effective, resulting in significant reductions in voiding pressure and post-void residual urine volumes although no significant changes have been noted in bladder capacity (Chancellor et al.1993a; Abdill et al. 1994; Chancellor et al. 1995; Seoane-Rodriguez et al. 2007; Abdul-Rahman et al. 2010). In addition, reduced incidence of UTIs and autonomic dysreflexia has typically been reported (Chancellor et al.1993a; Seoane-Rodriguez et al. 2007). Game et al. (2008) advocate for a trial period with a temporary stent early post-injury based on the percentage of patients (~30%) not choosing placement of a permanent stent or in whom the stent did not provide the expected results. This reversible management option is however, limited by the available materials for temporary stenting.

Chancellor and colleagues (1999) also conducted a RCT (n=57) comparing the outcomes associated with sphincterotomy as compared to placement of the stent (UroLome) prosthesis (Chancellor et al. 1999). This study was deemed a low quality RCT, largely because blinding and concealed allocation was not possible given the nature of the intervention. Similar measurement procedures and overall findings were noted as reported for the studies above (i.e., Chancellor et al. 1993c) with significant decreases in voiding detrusor pressure and post-void residual urine volumes and no significant changes reported for bladder capacity and no differences noted between sphincterotomy and stent for any measure at any time point (i.e., 3, 6, 12 and 24 months). The need for catheterization, initially required in 50% of the sphincterotomy group (n=26) and 71% of the stent group (n=31), was reduced to just 3, 4, 1, & 1 and 1, 0, 1 & 2 individuals respectively at 3, 6, 12 and 24 months respectively. There was little difference in subjective assessment of impact of bladder function on quality of life or in the incidence of complications between the treatment groups although those in the stent group spent less time in the hospital for the procedure.

Chancellor et al. (1993b) also have examined another procedure with similar rationale as that associated with sphincterotomy. This investigation involved a pre-post trial design (n=17) of transurethral balloon dilation of the external urinary sphincter. Again, similar methods were employed as the studies noted above and findings were also similar. Of all 17 patients previously managed by indwelling Foley catheter, 15 used condom catheters post-procedure and 2 voided on their own. Significant decreases were noted in voiding pressure (p=0.008) at all follow-up times (i.e., 3, 6 and 12 months). No changes were seen in bladder capacity (p=0.30) and significant reductions in post-void residual urine volumes (p<0.05) were seen at all follow-up times. Positive urine cultures (i.e., UTI) were noted in 15/17 prior to surgery but only in 5, 8 and 4 of the patients at 3, 6 and 12 months respectively. Subjective autonomic dysreflexia improved in all 9 individuals who had previously complained of this.

More recently, Patki et al. (2006) reported a small retrospective case series investigation (n=9) of implantation of an artificial urinary sphincter (AUS; American Medical System 800). This device has evolved over the years to where it is now easier to implant surgically, has a longer life and a higher success rate in achieving incontinence (~80% with more recent models). In this trial, all patients achieved successful incontinence with no self-reported leakage upon activation of the system. However, by 3 month follow-up, 2 patients reported significant recurrrent incontinence, with one implant being removed and the other being revised and by a mean follow-up of 105.2 months 5 of 9 implants have been successful with no revisions. Overall, more than half of the patients with working implants recorded higher maximum detrusor pressures although no upper tract change or deterioration in renal function was noted in any patient. A retrospective analysis in 2009 by Bersch et al. of individuals (n=51) who underwent implantation of an artificial sphincter at the bladder neck using a port instead of a pump suggested this approach to be highly successful, reliable, safe and cost-effective treatment option (even with implant revisions). Additionally, a retrospective review by Chartier-Kastler et al. (2011) determined an AUS device was effective in restoring urinary continence in males, in the majority of cases reviewed, with a decrease in urethral erosion by placement of the device around the bladder neck, providing more credence to consideration for SCI patients.

Conclusion

  • There is level 4 evidence from a single case-series study that sphincterotomy is effective in reducing episodes of autonomic dysreflexia associated with inadequate voiding.
  • There is level 4 evidence from a single case-series study that sphincterotomy, as a staged intervention, can provide long-term satisfactory bladder function.
  • There is level 2 evidence from a single low-quality RCT but supported by level 4 studies that both sphincterotomy and implantation of a sphincteric stent are effective in reducing incontinence, with little need for subsequent catheterization, and both treatments are associated with reduced detrusor pressure and reduced post-void residual volume but not with changes in bladder capacity. The only significant difference in these 2 treatments was the reduced initial hospitalization associated with the stent, given the lesser degree of invasiveness.
  • There is level 4 evidence that implantation of a sphincteric stent may result in reduced incidence of UTIs and bladder-related autonomic dysreflexia over the short-term although several studies have demonstrated the potential for various complications and subsequent need for re-insertion or another approach over the long-term.
  • There is level 4 evidence from a single long-term follow-up study of those having a previous sphincterotomy that the incidence of various upper and lower tract urological complications may be quite high.
  • There is level 4 evidence from a single case-series study that advocates for placement of a temporary stent early after injury as a reversible option that allows patients to choose from the range of permanent stent placement to less invasive bladder management methods such as intermittent catheterization.
  • There is level 4 evidence based on a single study that transurethral balloon dilation of the external sphincter may permit removal of indwelling catheters in place of condom drainage, and also may result in reduced detrusor pressure and post-void residual volume but not with changes in bladder capacity.
  • There is level 4 evidence based on 2 studies that implantation of an artificial urinary sphincter may be useful in the treatment of incontinence in SCI but further study is required.
  • There is level 4 evidence from a single pre-post study that transurethral incision of the bladder neck may be useful in bladder neck and voiding dysfunction. 
  • Surgical and prosthetic approaches (with a sphincterotomy and stent respectively) to allow bladder emptying through a previously dysfunctional external sphincter both seem equally effective resulting in enhanced drainage although both may result in long-term upper and lower urinary tract complications.

    Artificial urinary sphincter implantation and transurethral balloon dilation of the external sphincter may be associated with improved bladder outcomes but require further study.

Other Miscellaneous Treatments

In addition to those noted in the previous sections, there are a variety of other approaches that have been investigated to address the consequences of neurogenic bladder associated with SCI. These include the use of desmopressin acetate (DDAVP) as an adjuvant therapy to manage the effects of an overactive bladder otherwise refractory to conventional treatment such as nocturnal enuresis (i.e., night-time emission of urine) or the requirement for too frequent catheterizations. DDAVP is a synthetic analogue of antidiuretic hormone (ADH) most commonly administered by intravenous infusion for treatment of bleeding disorders. It can also be taken in the form of a pill or intranasal spray for reducing urine production as in the present application (Chancellor et al. 1994; Zahariou et al. 2007). DDAVP is thought to bind to V2 receptors in renal collecting ducts to increase water reabsorption.

Others have employed alternative approaches such as electroacupuncture (Cheng et al. 1998) or nerve crossover surgery / spinal root anastomoses (Livshits et al. 2004; Lin et al. 2008; Lin et al. 2009) to enhance recovery of bladder function.

Table: Other Miscellaneous Treatments

Discussion

Zahariou et al. (2007) and Chancellor et al. (1994) conducted a pre-post (n=11) and a case series (n=7) investigation retrospectively to investigate the use of intranasal DDAVP as an alternative therapy to reduce urine production in the hopes of reducing nocturnal emissions or reducing the need for overly frequent catheterization during the day. In each case, DDAVP was employed as an adjuvant therapy in addition to standard therapies of anticholinergics and intermittent catheterization which had resulted in less than satisfactory results. With use of DDAVP just before bedtime, Zahariou et al. (2007) reported a statistically significant increase in urine production rate during the day (p<0.001) and a decrease in nocturnal urine production (p<0.001). After DDAVP treatment, participants had reduced or complete elimination of nocturnal enuresis (Chancellor et al. 1994; Zahariou et al. 2007). In addition, the proportion of persons requiring clean intermittent catheterizations in the night while still maintaining continence was greatly reduced (Zahariou et al. 2007) and 3 individuals used DDAVP during the day at work and were able to achieve an additional 3.5 hours between catheterizations (Chancellor et al. 1994). These improvements persisted for a mean of 12 months. These small scale studies provides only preliminary evidence and encourages further study, although DDAVP is in fairly widespread use for SCI-related neurogenic bladder.

Another adjunctive therapy that has been investigated is the use of electroacupuncture. For example, Cheng et al. (1998) conducted a RCT (n=60) investigating the effectiveness of electroacupuncture administered in combination with conventional bladder management method (i.e., intermittent catheterization, tapping and trigger point stimulation) as compared to those not receiving electroacupuncture. Their primary outcome measure was the time to achieve bladder balancing which was defined as the time when 1) the patient could easily pass adequate urine at low pressure, 2) residual urine of approximately 100 ml or less and 3) absent UTIs. Although employing a randomized, controlled design, some limitations (i.e., lack of blinding, concealed allocation or intent to treat) constrained the level of evidence assigned to this trial (i.e., Level 2). Regardless, those receiving electroacupuncture had a reduced time to achieve bladder balancing for both those with upper motor lesions (p<0.005) and lower motor neuron lesions (p<0.01). In addition, if electroacupuncture was started within 3 weeks of SCI, bladder balancing was achieved sooner than those which started after 3 weeks (p<0.005).

Reports regarding microanastamosis to reinnervate the paralyzed bladder reveal recovery of neurogenic bladder dysfunction. These include surgical anastomosis of the intercostal nerve (Livshits et al 2004; n=11), T11 nerve root (Lin et al 2008, n=10), L5 nerve root (Xiao et al 2003, n=15) or the S1 nerve root (Lin et al 2009, n=12) to the S2 or S3 spinal nerve roots. Mean follow-up of patients was between 2 to 3 years and restitution of bladder function was observed in the majority of patients. Significant results were reported for pre and post-surgical findings including reduced bladder capacity with increased urine volume under increased force of detrusor contractions and increased voiding pressure. There was also reduced residual urine volume and both detrusor tone and sphincter resistance were increased. Results from individual subjects in Livshits et al (2004) were presented for each of these showing consistency across these measures although statistical analysis techniques were inappropriate consisting of individual Wilcoxon signed rank tests for each variable. Patient self-report measures showed increases within a few months following surgery. Similar findings were evident in 100/67/75% of patients undergoing T11/L5/S1 microanastamosis respectively (Lin et al 2009, Xiao et al 2003, Lin et al 2008). Full recovery of renal function and an absence of urinary tract infections was observed at follow-up (i.e., 6-18 months). Important considerations of this surgical approach are that it is far more invasive than other approaches (i.e., indwelling catherization); and patients do not regain the bladder sensation that contributes to quality of life (i.e., sensing urgency and timing of micturition). In particular, accidental voiding may be triggered by unintentional dermatomal stimulation or Achilles tendon stretch. Furthermore, considering the potential for up to 30% failure rates and serious side effects (i.e. neuromas) this invasive procedure must be weighed cautiously against other approaches to treatment of bladder dysfunction.

Conclusion

  • There is level 2 evidence from a single study that early treatment with electroacupuncture may shorten the time that it takes to develop low pressure voiding /emptying with minimal residual volume, when combined with conventional methods of bladder management.
  • Level 4 evidence from two studies suggests that intranasal DDVAP may reduce nocturnal urine production with fewer night-time emissions and also may reduce the need for more frequent catheterizations in persons with SCI with neurogenic bladder that is otherwise unresponsive to conventional therapy.
  • There is level 4 evidence from four studies that nerve crossover surgery (anastomosis of more rostral ventral nerve roots to S2-S3 spinal nerve roots) may result in improved bladder function in chronic SCI. 
  • Early electroacupuncture therapy as adjunctive therapy may result in decreased time to achieve desired outcomes.

    Intranasal DDVAP may reduce nocturnal urine emissions and decrease the frequency of voids (or catheterizations).

    Anastomosis of the T11, L5 or S1 to the S2-S3 spinal nerve roots may result in improved bladder function in chronic SCI.

Detrusor Areflexia

Detrusor areflexia is seen most commonly in cauda equina lesions where the sacral reflex is disrupted. It can occasionally occur at other levels of spinal lesions. The clinical manifestation of this results in an inability for the bladder to empty completely or at all, leading to overdistension and stasis. Additionally, there is frequently incontinence due to lack of external sphincter tone, most often due to increased abdominal pressure on the bladder (i.e. stress incontinence). This can be especially problematic in persons with paraplegia that may require high valsalva forces for activities such as transferring from wheelchairs.

Unfortunately, there is a great paucity of research examining the impact and treatment of detrusor areflexia. Although the goals remain the same as with overactive bladder in SCI, (i.e., avoiding incontinence, stasis, UTI’s, and upper urinary tract damage, etc.), these goals may be achieved differently. In general, the goal is either: 1) stopping leakage and improving storage with medications and intermittent catheterization, or 2) improving emptying, either voluntarily in the incomplete injury, and/or into condom drainage in the person with more severe neurogenic bladder impairments. However, further discussion on detrusor areflexia will not occur in this chapter given the extremely sparse evidence base. It should be noted that in some studies described in the sections pertaining to DESD therapy there may have been mixed samples in which a few subjects with detrusor areflexia might have participated in addition to those with detrusor overactivity. In one instance, subjects with detrusor areflexia comprised all study participants providing level 4 evidence from a single case series (n=10) for the surgical anastomosis of the T11 ventral nerve root to the S2-S3 ventral nerve roots in improving bladder function (e.g., Lin et al. 2008 in Table 13.16 for Other Miscellaneous Treatments). 

Urinary Tract Infections

Defining Urinary Tract Infections

Urinary tract infections (UTIs) are a common secondary health condition following SCI and a major cause of morbidity (Charlifue et al. 1999; Vickrey et al. 1999). There are numerous ways that UTIs have been defined within individual studies with respect to either identifying the presence of UTIs and/or establishing treatment success. Although this diversity exists across studies, the criteria identified at the National Institute on Disability Rehabilitation Research (NIDRR) sponsored National Consensus Conference on UTI (1992) have become generally accepted standards for UTI definition. These designate a UTI as indicative of significant bacteriuria with tissue invasion and resultant tissue response with some or all of the following signs and / or symptoms:

  • Leukocytes in the urine generated by the mucosal lining,
  • Discomfort or pain over the kidneys or bladder, or during urination,
  • Onset of urinary incontinence,
  • Fever,
  • Increased spasticity,
  • Autonomic hyperreflexia,
  • Cloudy urine with increased odor,
  • Malaise, lethargy, or sense of unease.

Significant bacteriuria varies according to the method of urinary drainage and is defined by the following criteria: ≥102 colony-forming units of uropathogens per milliliter (cfu/mL) in catheter specimens from persons on intermittent catheterization, (b) ≥104 cfu/mL in clean-voided specimens from catheter-free men using condom catheters, c) any detectable concentration of uropathogens in urine specimens from indwelling or suprapubic catheters, and d) ≥105 cfu/mL for spontaneous management. Treatment of asymptomatic bacteriuria is not recommended as it has been shown not to be effective and can actually create antimicrobial resistance.

Detecting and Investigating UTIs

Detecting a UTI is the first stage towards successful treatment. Identification of symptoms by the patient is a critical first step in this detection; however, in a prospective case review undertaken by Linsenmeyer and Oakley (2003) only 61% (90/147) of patients were able to correctly predict the presence of a UTI based on their symptoms. Other methods of detection include urine chemical dipsticks which provide an indication of the presence of nitrites and leukocytes with the benefit of a providing a quick turnaround (Faarvang et al. 2000; Hoffman et al. 2004). However, the primary approach and gold standard is the microbiological evaluation of urine bacterial culture. As noted above, organizations such as NIDRR have defined UTIs at least in part on the results of laboratory investigations documenting the presence, amount and type of bacterial growth that occurs with an infection. This also results in the identification of the antibiotic(s) for which the bacteria species may be susceptible (i.e., sensitivity). Furthermore, it has been noted that 33% of SCI UTIs are polymicrobial (Dow et al. 2004). The clinician must then decide between a limited or full microbial investigation in selecting the appropriate treatment. The obvious benefit of a full microbial investigation (i.e. accuracy) is offset by potentially adverse effects due to the time delay for the bacterial sensitivity results and the cost of a full investigation. The studies reviewed in the present section examine specific issues associated with the laboratory investigation of UTIs and how these might impact treatment. 

Table: Investigating UTIs

Discussion

As noted above, laboratory investigation of suspected UTI using microbiological analysis of urine cultures is important for diagnosing UTI and also for guiding treatment. For example, Shah et al. (2005), Hoffman et al. (2004) and Tantisiriwat et al. (2007) reporting centre-based results under a variety of study designs, noted Enteroccoccus species, K. pneumonia, E coli, Pseudomonas aerginosa, Staphlococcus aureus and Proteus mirabilis as among the most common species of bacteria present in urine from those suspected of having a UTI. Antibiotic sensitivity tests are then conducted to determine if these bacteria are susceptible to specific antibiotics. For example, Tantisiriwat et al. (2007) noted that of the antibiotics tested, E. coli was most susceptible to amikacin (96.1%), ceftazidime (88.9%), and cetriaxone (75%). The efficacy of specific antibiotics investigated in the SCI literature will be summarized in subsequent sections.

However, given the cost and the time spent before results can be obtained with bacterial culture (e.g., from 18-48 hours), simpler screening methods have been developed for assessing the presence of a UTI. One of these methods involves using a urine “dipstick” which signifies the presence of nitrates or the presence of leukocyte esterase (LE) respectively as a potential indicator of UTI. The results of investigations into the sensitivity and specificity of these dipstick tests in predicting UTI in patient populations other than SCI have been mixed so Hoffman et al. (2004) conducted an investigation to compare dipstick results for Nitrites and LE to urine culture results where each test was conducted monthly over a 5 year period in a community-based SCI sample (n=56). Using NIDRR criteria for UTI, 81% of the total 695 samples collected over the study period met criteria for bacteriuria, and of these, 36% met criteria for a positive UTI. In general, sensitivity (i.e., the ability to correctly identify significant results) was relatively low at 63% even when either the LE or nitrate dipstick was positive and specificity (i.e., the ability to correctly identify samples without significant bacteria) was 89% or higher for any combination of test. When compared to the ability to predict UTIs, the dipstick sensitivity remained relatively low at 63% and specificity was also low at 52% for any combination of dipstick test. Overall results suggest using dipstick testing as a treatment guide could result in inappropriate or delayed treatment and the study authors suggested that individuals with SCI with suspected UTI should be evaluated with urine culture and not dipstick testing (Hoffman et al. 2004). However, a separate investigation comparing positive and negative predictive values for dipstick testing as compared to leukocyte microscopy relative to culture-derived bacteriuria determined that either method was equally effective with reasonable prediction rates of approximately 80% for each alone or in combination (Faarvang et al. 2000).

Practicality and cost savings in UTI prevention and treatment may not have been the prime motive in an investigation by Darouiche et al. (1997), but they did find that an adequate clinical response to treatment was not significantly different as a result of limited vs full microbial investigation. Limited investigations were conducted by examining colony morphology, appearance on Gram-stain, catalase test and oxidase test without organism identification and antibiotic susceptibilities. Rather, antibiotic selection was based on recognized hospital-based patterns of antibiotic susceptibilities. As well, the cost savings, at an average of $183 US per patient, was not significantly less but indicated a trend (p=0.18) associated with limited vs full investigation. Although this provides level 1 evidence in favour of deferring to a limited microbial investigation for SCI UTI treatment selection, the sample size was small (N=15) and warrants further study. It is also unclear from this study if the results are transferable to anything but an inpatient hospital unit (i.e., not community-based patients) and if treatment is determined in part by relying on the experience of the clinical team in determining treatment.

The results of clinical laboratory analysis are also prone to contamination from a variety of practical issues. For example, sample deterioration between the time of sampling and processing is controversial. Horton et al. (1998) conducted a blinded RCT to investigate the effects of refrigeration on urinalysis and culture results. Samples were split and analyzed at 4 (“fresh”) and 24 (“refrigerated”) hours post-refrigeration. The bacterial counts of “mixed” organisms (p=0.10) and Staph aureus (p=0.66) were altered with refrigeration but no changes in colony counts would have altered the treatment regimen chosen based on urinalysis or culture results. This level 1 evidence provides a level of confidence for urine samples refrigerated (up to 24 hours) prior to analysis.

In another investigation of a narrower issue involving potential contamination, Shah et al. (2005) demonstrated that the number of clinically significant organisms (≥105 cfu/mL) detected by urine culture were reduced in SCI inpatients with indwelling or suprapubic catheters suspected of having a UTI when the catheter was changed just prior to urine collection as compared to those where it was left unchanged (p=0.01). This practice also resulted in a savings of $15.64 per patient.

Conclusion

  • Level 1 evidence based on a single RCTon SCI inpatients suggests that both limited and full microbial investigation result in adequate clinical response to UTI treatment with antibiotics. Therefore the cost savings attributed to a limited microbial investigation favours this practice in the investigation of UTI although more rigorous investigation of the patient outcomes and attributed costs is needed.
  • There is limited level 1 evidence from a single investigation that refrigeration (up to 24 hours) of urine samples prior to sample processing does not significantly alter urinalysis or urine culture results in SCI patients.
  • There is limited level 2 evidence from a single investigation that fewer false positive tests showing bacteriuria occur if indwelling or suprapubic catheters are changed prior to collection for urine culture analysis.
  • There is conflicting level 4 evidence from two investigations concerning whether dipstick testing for nitrates or leukocyte esterase is recommended to guide treatment decision-making.
  • Both limited and full microbial investigation may result in adequate clinical response
    to UTI treatment with antibiotics.

    Indwelling or suprapubic catheters should be changed just prior to urine collection so as to limit the amount of false positive urine tests.

    Urinalysis and urine culture results of SCI patients are not likely to be affected by sample
    refrigeration (up to 24 hours).

    It is uncertain if dipstick testing for nitrates or leukocyte esterase is useful in screening for bacteriuria to assist treatment decision-making.

Non-Pharmacological Methods of Preventing UTIs

The method of bladder management one selects is a primary factor in reducing the risk of UTI in persons with SCI (Trautner & Darouiche 2002). The method chosen should minimize access to the urinary system by foreign bodies and reduce their potential for continued residence by draining the bladder effectively. Most SCI-related research for UTI prevention by these means has been conducted on various techniques for intermittent catheterization and these types of studies are summarized in Table 13.18. Different coatings have been applied to catheters to minimize various complications associated with catheterization and neurogenic bladder and Table 13.19 outlines studies investigating the effect of hydrophilic catheters on UTI prevention. Finally, Table 13.20 summarizes studies that compare intermittent catheterization to other bladder management methods or use aids to augment the use of a particular bladder management method with a goal of preventing UTIs. 

Table: Intermittent Catheterization and Prevention of UTIs

Discussion

During inpatient rehabilitation, intermittent catheterization is the preferred method of bladder management for most cases and several prospective studies have compared sterile techniques with traditional or clean techniques of intermittent catheterization (Charbonneau-Smith 1993; Prieto-Fingerhut et al.1997; Moore et al. 2006). Notably, Moore et al. (2006) and Prieto-Fingerhut et al. (1997) employed RCT designs and showed no statistically significant differences in the number of UTIs occurring in patients using the sterile technique vs the clean technique. Conversely, Charbonneau-Smith (1993) conducted a prospective trial and did find significantly reduced UTI rates for a sterile “no-touch” method as compared to historical controls undergoing a traditional sterile method, although the nature of the historical comparison provides the possibility of confounding variables also affecting this result. Each author noted the greater expense associated with the sterile approach, making it the less attractive option in the absence of evidence for improved positive outcomes.

As with all aspects of rehabilitation, a primary goal of bladder training within an inpatient stay is the goal of patient independence and self-care. Wyndaele and De Taeye (1990) conducted a case control study (n= 73) in which the incidence of UTIs was examined following introduction of an initiative to promote self-catheterization among those with paraplegia on an SCI unit. Prior to this, catheterization was conducted by a specialized catheter health care team using a non-touch technique. Neither UTI rates nor the proportion of people achieving a state of bladder balance or those encountering complications of urethral trauma were significantly different between these 2 approaches. Interestingly, the introduction of patient self-catheterization also seemed to be a factor in the patients being ready for home visits much sooner in their rehabilitation stay.

Less information exists on the continued use of intermittent catheterization for individuals as they move into the community and live with SCI for a prolonged period of time. A case control investigation was conducted by Yadav et al. (1993) comparing UTI incidence rates between those using a clean intermittent catheterization technique during inpatient rehabilitation with another group of patients continuing to use the same bladder management method and living in the community for 1-12 years. Similar rates of UTI (termed acceptably low by the authors) were found in both samples although there were differences in the types of bacteria causing UTIs between the SCI rehabilitation unit and the community.

Regardless of the approach to bladder management, and even if intermittent catheterization is used, the rate of UTI in the SCI population is still elevated relative to a population with neurologically normal functioning bladders This is thought to be partly due to the residual volume of urine that may persist in the bladder following intermittent catheterization. Jensen et al. (1995) conducted a study in inpatient rehabilitation (n=12) correlating UTI incidence over the rehabilitation period with the average residual urine volume after intermittent catheterization. Correlations between UTIs and residual volumes were low and suggested little relationship or as the authors point out it may have been that residual volumes would have had to be reduced to negligible values before UTI incidence would have been reduced as opposed to the mean values of 40 ± 11 ml (hyperactive bladder) or 19 ± 7 ml (hypoactive bladder) seen in this study.

Conclusion

  • Level 2 evidence based on two RCTs suggests no difference in UTI rates between sterile vs clean approaches to intermittent catheterization during inpatient rehabilitation, however, using a sterile method is significantly more costly.
  • There is limited level 4 evidence from a single study that there is no difference in UTI rates between intermittent catheterization conducted by the patients themselves or by a specialized team during inpatient rehabilitation.
  • There is limited level 4 evidence from a single study that similar rates of UTI may be seen for those using clean intermittent catheterization during inpatient rehabilitation as compared to those using similar technique over a much longer time when living in the community.
  • There is limited level 4 evidence from a single study that differences in residual urine volume ranging from 0-153 ml were not associated with differences in UTI during inpatient rehabilitation.
  • Sterile and clean approaches to intermittent catheterization seem equally effective in minimizing UTIs in inpatient rehabilitation.

    Similar rates of UTI may be seen with intermittent catheterization as conducted by the patients themselves or by a specialized team during inpatient rehabilitation.

    Similar rates of UTI may be seen with intermittent catheterization, whether conducted in the short-term during inpatient rehabilitation or in the long-term while living in the community.

    UTIs were not associated with differences in residual urine volumes after intermittent catheterization.

Table: Intermittent Catheterization using Specially Coated Catheters for Preventing UTIs

Discussion

Another approach used to reduce the incidence of UTI associated with catheterization in patients with neurogenic bladder involves the application of coatings to the catheter (Giannantoni et al. 2001; Vapnek et al. 2003; De Ridder et al. 2005; Cardenas & Hoffman 2009; Cardenas et al. 2011). For example, Giannantoni et al. (2001) employed a double-blind, crossover RCT design (n=18) to examine the difference between a pre-lubricated, nonhydrophilic Instantcath catheter as compared to a conventional polyvinyl chloride (PVC) silicon-coated Nelaton catheter with respect to the occurrence of UTIs and urethral trauma. The subjects were randomized to 1 of 2 groups which tried each catheter for a period of 7 weeks in an A-B, B-A design. Both incidence of UTIs (p=0.3) and presence of asymptomatic bacteriuria (p=0.024) were significantly reduced for the pre-lubricated catheter vs the conventional PVC catheter. Perhaps most interesting, 3 subjects requiring assistance with the conventional catheter became independent with the pre-lubricated catheter, although it was not reported if these individuals were in the group using the conventional catheter initially or lastly. The existence of an order effect (or not) for any of the measures was not reported. In terms of general satisfaction with use, subjects rated the pre-lubricated catheter significantly higher than the conventional catheter with respect to comfort, ease of inserting and extracting, and handling.

A similar finding of reduced incidence of UTIs (p=0.02) was reported by De Ridder et al. (2005), but in this case the reduction was associated with a hydrophilic catheter as compared to the conventional PVC catheter. This multi-centre investigation also employed a RCT design (N=123) but had several methodological problems that likely constrained the potential utility of the results. Most significant was a high drop-out rate (54%) with slightly more individuals not completing the study from the hydrophilic catheter group. A probable cause for many of these drop-outs was the lengthy treatment period of 1 year during which many individuals were likely to improve bladder function such that intermittent catheterization was no longer required. There were no other significant differences noted between the two groups including the number of bleeding episodes or occurrence of hematuria, leukocyturia and bacteriuria. More individuals expressed greater satisfaction with various aspects of the hydrophilic catheter, although these differences were also not significant. A reduced incidence of hematuria and a significant decrease in UTI incidence was also reported by Vapnek and Maynard (2003), when hydrophilic vs non-hydrophilic catheter use was compared in a 12 month study of 62 patients (n=49 completed).

Reduced numbers of treated UTIs were reported by Cardenas & Hoffman (2009) with the use of hydrophilic catheters vs standard nonhydrophlic catheters even though no difference was reported between the 2 groups of self-IC SCI patients for number of symptomatic UTIs. Furthermore, lubrication was more beneficial for men since women on self-IC were more likely to develop UTIs regardless of catheter type. Although this study may have been underpowered, it is important to note that the drop out rate was just under 20% as compared to almost 54% in the DeRidder et al (2005) study with only 57/123 subjects remaining at the end of year 1. The Cardenas & Hoffman (2009) study also included women which allowed for potential gender differentiation in the effect of hydrophilic catheter use. Although females accounted for 29% of the participants, an n=16 should invoke caution when interpreting the data.

More recently, Cardenas et al.(2011) showed that time to the first antibiotic-treated symptomatic UTI in acute SCI patients (less than 3 months injured for inclusion) could be delayed by opting for a hydrophilic coated catheter as compared to an uncoated catheter. However effects disappeared when first months after institutional discharge were included in the analysis. Participants and/ or caregivers reported significantly higher satisfaction (P=0.007) with the hydrophilic coated catheter versus the uncoated however no differences were found in a similar evaluation by nursing staff. This largest RCT to date on this topic

Conclusion

  • There is level 1 evidence based on 1 RCT that pre-lubricated nonhydrophilic catheters are associated with fewer UTIs as compared to conventional Poly Vinyl Chloride catheters.
  • There is conflicting level 2 evidence based on 1 RCT that fewer UTIs may result with the use of hydrophilic catheters as compared to conventional PVC catheters.
  • There is level 2 evidence based on 2 RCTs that use of hydrophilic vs non-hydrophilic catheters are associated with fewer symptomatic UTIs treated with antibiotics even though the number of symptomatic UTIs are similar between groups.
  • A reduced incidence of UTIs or reduced antibiotic treatment of symptomatic UTIs have been associated with pre-lubricated or hydrophilic catheters as compared to standard non-hydrophilic catheters.

Table: Other Issues Associated with Bladder Management and UTI Prevention

Discussion

In addition to intermittent catheterization, the effects of other bladder management methods have been investigated with respect to their impact in preventing UTIs. In particular, intermittent catheterization has been compared to indwelling catheterization. Joshi and Darouiche (1996) report following a prospective controlled trial that the response to antibiotic, as indicated by reduced pyuria, is improved and can be assessed earlier in patients who utilize intermittent catheterization over those whose bladder drainage is reliant on suprapubic or indwelling foley catheters. All patients (n=29) experienced relief from appropriate antibiotic therapy after 3-4 days, but the level of residual pyuria was lowest at mid-therapy and after therapy completion in those patients using intermittent catheterization.

In another comparison study, Nwadiaro et al. (2007) conducted a retrospective comparison of indwelling urethral catheterization and suprapubic cystostomy on UTI prevalence in a predominately illiterate and impoverished population where intermittent catheterization is a less preferred option. Prevalence of UTI was significantly less in the group having a suprapubic versus indwelling urethral catheter (p<0.05). In addition, there was significantly less mortality with the suprapubic catheter (p<0.05) at 1 year post admission with UTI-related septicaemia the number one cause of death in these patients. Sugimura also looked at the incidence of complications in patients using suprapubic catheterization, and reported a 29% incidence of UTI’s, though there was no comparison group in this study. However, in Ku et al. (2005) no bladder management technique was found to be superior in protecting against pyelonephritis (simple UTI was not tracked as an outcome); instead, the presence of vesicoureteral reflux led to a 2.8 fold higher risk of pylonephritis than those without reflux. Reflux is most often associatiated with high pressure urine storage due to low compliance or high pressure voiding due to sphincter spasticity and obstruction. Thus actual bladder pathophysiology may have the largest affect on clinically significant infections with the caveat that in this study, the group with urethral catheterization did experience more total upper tract deterioration than other bladder management groups.

Lloyd et al. (1986) conducted a case control investigation reviewing a group of 204 SCI patients grouped according to urological management techniques as follows: A) intermittent catheterization within 36h of injury, B) suprapubic trocar drainage within 36 h of injury, C) urethral catheter drainage for >36h prior to intermittent catheterization, D) indwelling urethral catheter drainage throughout and after discharge from hospital and E) intermittent catheterization placed in community hospital. Overall, these authors found that the method of initial bladder management does not affect the incidence of UTI, genitourinary complications or frequency of urological procedures at 1 year after injury. The only exception was group D who had a greater rate of UTIs as a result of the prolonged placement of indwelling urethral catheter drainage throughout and after discharge from hospitalization. It should be noted that individual variations in bladder management methods following the initial method and up to the one year follow-up were not accounted for in this investigation representing a potential major confound.

As noted in several of these comparative investigations, complications occur most frequently in those with urethral catheterization. Despite this, many patients resort to using urethral catheterization for convenience or necessity, if hand dexterity is insufficient, or care givers unaffordable. Some investigators have suggested an approach to minimizing UTI when urethral catheterization is determined to be the most viable management approach. Darouiche et al. (2006) conducted a multicentre RCT of hospital inpatients (n=118) in which the effect of securing indwelling catheters with a device called the Statlock as compared to traditional means of catheter securement (i.e., tape, velcro strap, cath-secure, or nothing) was assessed. In addition to SCI, 10 subjects had multiple sclerosis. In this trial, there was a statistically non-significant trend for a lower rate of symptomatic UTI (p=0.16) and also a lower incidence of symptomatic UTI per 1000 device days (p=0.16) for those using this Statlock device versus the control group.

Condom catheters also can be a source of bacterial colonization, especially of the perineum, which has been suggested by Sanderson and Weissler (1990b) to be significantly correlated with bacteriuria in SCI individuals. By discontinuing night time use of an external condom drainage system in a prospective controlled trial involving SCI rehabilitation inpatients (n=119), Pseudomonas colonization of the urethra was found to be significantly reduced where Klebsiella colonization was not significantly affected (p<0.05) (Gilmore et al. 1992). Further, a 3rd group of patients did not use a condom drainage system at any time and colonization rates for both Pseudomonas and Klebsiella were significantly lower in this group at all sites tested (urethra, perineum and rectum) as compared to those using the external drainage system (p<0.05). However, the prevalence of bacteriuria caused by either gram-negative bacilli, was not reduced with either night-time or continuous disuse of an external condom drainage system.

Conclusion

  • There is level 2 evidence based on a single prospective controlled trial and supported by a case control study that intermittent catheterization may lead to a lower rate of UTI as compared to other bladder management techniques such as use of indwelling or suprapubic catheter.
  • There is level 3 evidence based on a single case control study that bladder management with a suprapubic as opposed to indwelling catheter may lead to a lower rate of UTI and reduced mortality in a poor, illiterate population where intermittent catheterization may not be viable as an approach to bladder management.
  • There is weak level 2 evidence based on a single low quality RCT that suggests that use of the Statlock device to secure indwelling and suprapubic catheters may lead to a lower rate of UTI.
  • There is level 2 evidence based on a single prospective controlled trial that suggests that removal of external condom drainage collection systems at night or for 24 hours/day might reduce perineal, urethral or rectal bacterial levels but have no effect on bacteriuria.
  • There is level 4 evidence based on a single case series that no bladder management method is advantageous in preventing pyelonephritis (though indwelling urethral catheterization does have the highest incidence of upper tract deterioration). However, the presence of reflux results in a 2.8 fold higher incidence of pyelonephritis.
  • Intermittent catheterization is associated with a lower rate of UTI as compared to use of indwelling or suprapubic catheter.

    The Statlock device to secure indwelling and suprapubic catheters may lead to a lower rate of UTI.

    Removal of external condom drainage collection systems at night or for 24 hours/day may reduce perineal, urethral or rectal bacterial levels but has no effect on bacteriuria.

    The presence of vesicoureteral reflux likely has a greater impact on development of significant infections than the choice of bladder management.

Pharmacological and Other Biological Methods of UTI Prevention

There are a variety of approaches that involve pharmaceuticals and other biological agents that have been examined for UTI prevention in persons with SCI - as is noted in several reviews on this topic (Biering-Sorensen 2002; Garcia Leoni & Esclarin De Ruz 2003). These include pharmacological approaches such as bacterial interference or antibiotic prophylaxis, the use of other biological agents such as antiseptic cleansing agents or the use of nutraceuticals such as cranberry in one form or another. 

Table: Bacterial Interference for Prevention of UTIs

Discussion

Bacterial interference has been touted as a promising approach to UTI prevention for the future (Biering-Sorensen 2002). In this approach, a group of bacteria that do not cause UTIs are introduced into the bladder which acts to limit the ability of other pathogens to effectively colonize the bladder and cause a symptomatic UTI. To date, the specific approach employed in studies in persons with SCI has been to colonize the bladder with E. coli 83972 (Hull et al. 2000; Darouiche et al. 2005; Prasad et al. 2009). Most notably, Darouiche et al. (2005) conducted a prospective, randomized, placebo-controlled, double-blind trial (n=27) in which they randomized persons with SCI of greater than 1 years duration and with a history of symptomatic UTIs to receive bladder inoculation of either E. coli 83972 or sterile normal saline at a 3:1 ratio. This was preceded by a one-week course of empirically selected antibiotics as it has been noted that successful colonization is more likely achieved with a sterile bladder (Hull et al. 2000). Patients were monitored over the following year with monthly urine cultures. The number of UTIs experienced by those with successful E. coli 83972 colonization had significantly fewer UTIs than those with saline inoculation or unsuccessful E. coli inoculation (1.6 vs 3.5 episodes/year, p =0.036). The period during which the bladder remained colonized by E. coli 83972 was variable among study participants with only 13 of 21 patients being successfully colonized for at least 1 month, 4 of these remaining colonized for the entire 1 year study period and 9 losing E. coli after an average of 3.5 months. It should be noted that statistical comparisons were made between those with successful colonization (n=13) vs those inoculated with saline (n=6) combined with those not successfully inoculated (n=8). Only 1 of the 13 participants successfully inoculated developed a UTI while E. coli 83972 was in the bladder and this was associated with another organism (P. aeruginosa). No adverse events were obtained with the E. coli 83972 inoculations although 1 person in the saline group developed autonomic dysreflexia which subsided post-inoculation.

Prasad et al. (2009) using a less robust pre-post study design, also reported that preinoculation antibiotics improved inoculation rates, that rates of UTI went down during the period of colonization, and that colonization with E.coli 83972 is safe.

A longer period of colonization was achieved in the pre-post trial conducted by Hull et al. (2000) in which 21 individuals with longstanding SCI (> 18 months) with a history of symptomatic UTI over the preceding year were inoculated with E. coli 83972 following a course of appropriate antibiotics for 5-7 days. Persistent colonization of greater than 1 month was achieved in 13 study participants with mean colonization duration of 12.3 months (range 2-40 months). No participant sustained a UTI while colonized with E. coli even though these same individuals had a mean of 3.1 UTIs over the previous year. UTIs were noted in 4 of 7 persons not successfully colonized and at a rate of 3.5 UTIs/year for the months following loss of colonization in those where E. coli 83972 was no longer found in the bladder. The overall results from these three studies point to a strong effectiveness associated with this approach while the bladder remains colonized but that more work is required to enhance the rate of successful inoculation and to examine methods for sustaining the period of colonization.  

Conclusion

There is level 1 evidence based on a single RCT and supported by two level 4 investigations that bacterial interference in the form of E. coli 83972 bladder inoculation may prevent UTIs.

  • E. coli 83972 bladder inoculation may prevent UTIs.

Table: Antibiotic Prophylaxis of UTIs

Discussion

Several investigations have been conducted which explore the effectiveness of a prophylactic antibiotic approach although cost and conflicting results along with issues of adverse events and increasing likelihood of enhancing resistant organisms have led reviewers to not recommend this approach for routine use (Garcia Leoni & Esclarin De Ruz 2003). Although researchers and clinicians have reservations about this approach, an obvious and important variable is the specific antibiotic that is used for prophylaxis. For the most part investigations in SCI patients have involved different dosages and regimens of orally administered ciprofloxacin or co-trimoxazole (trimethoprim-sulfamethoxazole or abbreviated as TMX-SMX) as prophylactic measures.

An RCT comparing low-dose, long-term treatment with ciprofloxacin (100mg each night) vs placebo concluded that ciprofloxacin prophylaxis for up to 39 months resulted in a marked reduction from the pre-study infection rate. (p<0.00005, corrected) with no severe side effects and only 1 instance of ciprofloxacin resistant E. coli found in the feces of 1 patient (Biering-Sorensen et al. 1994). Another RCT involved a 3 day course of ciprofloxacin (500 mg bid) or suitable placebo as a pre-cursor to urodynamic investigation (Darouiche et al. 1994), which has been associated with subsequent development of UTI (Pannek & Nehiba 2007). Of those receiving ciprofloxacin, none had a symptomatic UTI at the study follow-up visit (3-5 days post urodynamic testing), whereas 3 of 22 study participants (14%) in the placebo group developed a symptomatic UTI. This finding was statistically nonsignificant (p=0.24), but the trend for reduced UTI incidence and the fact that no subjects in the treatment group actually developed a UTI suggests that a study with greater power would be required to demonstrate the benefit of pre-urodynamic testing prophylaxis more conclusively.

Conflicting results have been obtained across separate controlled trials conducted in individuals undergoing acute SCI inpatient rehabilitation of sustained (i.e., > 3 months) prophylaxis with TMP-SMX. Gribble and Puterman (1993) reported that oral administration of a TMP (40mg) - SMX (200mg) formulation once daily was found to significantly reduce frequency and relapse rates of bacteriuria (p=0.0001) and symptomatic urinary tract infection (p=0.0003) in persons with recent SCI using intermittent catheterization for bladder management (n=129). Conversely, Sandock et al. (1995) reported on an investigation of patients at least 6 months post-injury within an inpatient SCI rehabilitation program in which the standard of care was to prescribe TMP-SMX liberally as a prophylaxis. This practice was stopped for the purpose of conducting a prospective controlled trial in 1 of 2 units and it was noted that there was no significant difference in the number of symptomatic UTIs between those stopping vs those continuing suppressive therapy (0.043 vs 0.035 UTIs/week, p>0.5). In addition, there was a significant decrease in the emergence of TMP-SMX resistant asymptomatic bacteriuria in the patients stopping suppressing therapy (78.8% vs 94.1%, p<0.05). This latter finding was also consistent with that noted by Gribble and Puterman (1993) who noted this, along with TMP-SMX related adverse events as serious limitations of TMP-SMX prophylaxis therapy. Reid et al. (1994b) also showed an inability of a higher dose of TMP (160mg)-SMX(800mg) to reduce rates of symptomatic UTI within a prospective controlled trial conducted on a rehabilitation unit in patients using intermittent catheterization for bladder management.

Given the conflicting findings noted above and in other patient groups, a novel approach to UTI prevention in SCI patients was undertaken by Salomon et al. (2006). After a prospective, pre-post study with 2 year follow-up, they concluded that a weekly oral cyclic antibiotic (WOCA) program was beneficial in preventing UTI in SCI patients, decreasing antibiotic consumption and decreasing the number and length of hospitalizations, without severe adverse events or the emergence of multi-drug resistant (MDR) bacteria. The WOCA regimen involved alternating between two antibiotics, administered once per week over at least 2 years. The specific antibiotics selected as prophylaxis were customized to the patient, chosen based on allergy and antimicrobial susceptibility. The most frequent combination of antibiotics utilized were trimethoprim / sulfamethoxazole and cefixime (30%) followed by cefixime and nitrofurantoin (25%). The combination of antibiotics was modified in 40% of the patients once, 20% twice and 10% on three occasions during the follow-up. Salomon et al. (2009) expanded on earlier work specifically to employ a WOCA program in pregnant women with SCI. In this study, UTI rate during pregnancy (which is commonly elevated) was significantly reduced, no complications were observed during delivery, and all newborns were a healthy weight (Salomon et al. 2009). This level 4 evidence for the effectiveness of WOCA in SCI UTI prevention, treatment and cost, and would serve well as guidance in design of a randomized, double-blind, placebo-controlled study to confirm these results.

Conclusion

  • There is level 1 evidence from a single RCT that low-dose, long-term ciprofloxacin may prevent symptomatic UTI.
  • There is level 1 evidence from a single RCT that TMP-SMX as prophylaxis may reduce symptomatic UTI rates although conflicting findings were obtained from 2 prospective controlled trials. The potential for emergence of drug resistant bacteria and TMP-SMX related adverse events further limit the potential use of TMP-SMX for prophylaxis.
  • There is level 4 evidence from a single study that suggests weekly oral cyclic antibiotic use, customized as to individual allergy and antimicrobial susceptibility, may be effective for UTI prevention in SCI patients, and UTI reduction in pregnant patients.
  • Ciprofloxacin may be indicated for UTI prophylaxis in SCI but further research is needed to support its use.

    Long-term use of TMP-SMX is not recommended for sustained use as a suppressive therapy for UTI prevention.

    A weekly oral cyclic antibiotic, customized to the individual, may be beneficial in preventing UTI in SCI.

Table: Antiseptic and Related Approaches for Preventing UTIs

Discussion

It is generally accepted that good hygiene practices are an important element in UTI prevention. Therefore, it is a natural extension to expect that antiseptic agents applied either directly to the bladder or to potential vectors of indirect transference might be effective in UTI prevention. Accordingly, Sanderson and Weissler (1990b) found that perineal colonization of SCI individuals was significantly correlated with bacteriuria and may be associated with contamination of the environment and indirectly of the hands of patients and staff. As a result of this finding, this group further examined the effect of chlorhexidine antisepsis on bacteriuria, perineal colonization and environmental contamination in spinally injured patients requiring intermittent catheterization (Sanderson & Weissler 1990a). In male patients not receiving antibiotics, daily body washing in chlorhexidine and application of chlorhexidine cream to the penis after every catheterization significantly reduced bacteriuria to 60% from 74% in patients who were only washed with standard soap, although the effect was not as strong as that delivered by treatment with appropriate antibiotics. Chlorhexidine antisepsis alone did not affect perineal coliform colonization or contamination of the environment although there was a trend for this effect (p<0.1). In essence, this antiseptic effect acted to amplify the bacteria-reducing effects of antibiotics.

Acidifying urinary pH for the prevention of UTIs is based on the established fact that pH reduction to ≤5.0 will inhibit growth of urinary E. coli (Shohl & Janney 1917), a prevalent pathogen in the urinary tract. An RCT conducted by Waites et al. (2006) on participants having indwelling or suprapubic catheter with existing bacteriuria and pyuria (n=89) compared sterile saline, acetic acid and neomycin-polymyxin solution bladder irrigants and demonstrated no effect on the degree of bacteriuria/pyuria, or development of antimicrobial resistance. Moreover, the twice daily bladder irrigation for 8 weeks resulted in a significant increase in urinary pH (p=0.01) for all groups to a range that was more favourable for the growth of E. coli (i.e., pH 6.0-7.0). Similarly, 2 weeks of phosphate supplementation or 2 gram per day of ascorbic acid for unspecified duration in SCI neurogenic bladder managed with IC or indwelling catheter have proved ineffective in acidifying urine or altering UTI rates (Schlager et al. 2005; Castello et al. 1996).

Feasibility of treatment is a valid issue for consideration as evidenced by the study conducted by Pearman et al. (1988). These investigators compared the use of trisdine with kanamycin-colistin, a medicated bladder instillation previously demonstrated to be effective to prevent bacteriuria and UTI in SCI (Pearman 1979). In this trial (n=18), they found no difference between incidence of bacteriuria in catheterized patients yet concluded that trisdine was preferred based on its stability at room temperature, association with a reduced likelihood for antibiotic-resistant bacteria and reduced cost compared to kanamycin-colistin. Although the latter are important factors for treatment choice, this study presents no evidence for preferential beneficial effects based on incidence of bacteriuria.

Another solution shown to have some promise in UTI prevention was studied as a combination therapy, both with antiseptic properties. Krebs et al. (1984) investigated the potential of a 5% hemiacidrin solution instilled as an intravesicular acidifying agent at each intermittent catheterization combined with oral administration of methenamine mandelate (2 mg) qid in persons undergoing SCI inpatient rehabilitation. As compared to individuals undergoing no bacterial prophylaxis, the pH of urine was significantly reduced (p<0.01) and there was a lower rate of symptomatic UTI (p<0.05) and less bacteriuria as indicated by a reduced number of positive cultures (p<0.001). The role of hemiacidrin solution alone in these findings remains uncertain.

 In contrast to these findings, as part of a double-blind, placebo-controlled RCT (n=305) conducted by Lee et al. (2007), oral methenamine hippurate (another formulation of methenamine as an antiseptic) was generally ineffective in preventing symptomatic UTIs. In this well-conducted large sample trial, active and placebo formulations (oral tablet) of both methenamine hippurate and a cranberry preparation were compared as to the occurrence of asymptomatic UTI (up to 6 months) as a primary end-point. There were no statistically significant effects with either treatment alone or in combination as compared to placebo.

These various conflicting results suggest the specific antiseptic agent, alone or in combination with others, and its mode of administration might be important in determining clinical effectiveness and that the practice of antiseptic bladder instillation along with other methods of delivery, dismissed as ineffective by some or in general practice by others (Pearman et al. 1988; Castello et al. 1996; Schlager et al. 2005; Lee et al. 2007), requires further study.

Conclusion

  • There is level 1 evidence based on a single RCT that oral methenamine hippurate, either alone or in combination with cranberry, is not effective for UTI prevention.
  • There is level 2 evidence from separate studies that bladder irrigation with trisdine, kanamycin-colistin or a 5% hemiacidrin solution combined with oral methenamine mandelate (2 mg qid) may be effective for UTI prevention.
  • There are varying levels of evidence that bladder irrigation with neomycin/polymyxin (level 1), acetic acid (level 1), ascorbic acid (level 2) or phosphate supplementation (level 4) is not effective for UTI prevention.
  • There is level 2 evidence based on a single low quality RCT that supports the use of daily body washing with chlorohexidine and application of chlorhexidine cream to the penis after every catheterization versus using standard soap to reduce bacteriuria and perineal colonization.
  • Oral methenamine hippurate, either alone or in combination with cranberry, is not effective for UTI prevention.

    The antiseptic agents delivered via bladder irrigation (5% hemiacidrin solution combined with oral methenamine mandelate) may be effective for UTI prevention, whereas others are not (i.e., trisdine, kanamycin-colistin, neomycin/polymyxin, acetic acid, ascorbic acid and phosphate supplementation).

    Daily body washing with chlorohexidine and application of chlorhexidine cream to the penis after every catheterization instead of using standard soap may reduce bacteriuria and perineal colonization.

Table: Cranberry for Preventing UTIs

Discussion

Cranberry (in various forms) is in widespread use for UTI prevention and many clinicians recommend it for this purpose. This remains the fact despite uncertainty as to its effectiveness, especially in persons requiring ongoing catheterization as reported in a recent Cochrane systematic review (Jepson & Craig 2008). However, also in 2008, Hess et al. conducted a study in which subjects were given either cranberry tablets or placebo for 6 months, and then crossed to the opposite arm, showing a significant reduction in UTI incidence for those on cranberry treatment. These authors chose a robust definition of UTI (see above), and explained in their conclusion that they presume the treatment effect arose from an effect on cell wall adherence to the uroepithelial cell wall, an effect that they propose takes > 1 month to develop. As such, shorter studies may fail to note benefit from cranberry treatment (see Linsemeyer et al. 2004). While Reid et al. 2001 is a short study, significant results were noted in biofilm load and bacterial adhesion (though this study was not designed to determine effect on significant UTI). These hypotheses help build our understanding of the potential mechanisms of action cranberry may have in preventing UTI.

As noted in the section on antiseptic agents above, Lee et al. (2007) conducted a well-designed double-blind, placebo-controlled RCT (n=305) that examined the effectiveness of cranberry tablets (1600 mg) for UTI prevention alone or in combination with oral methenamine hippurate (2 g). Neither treatment alone or in combination was effective in preventing symptomatic UTIs as assessed over a 6 month study period. This rigorous study incorporated intention-to-treat and multiple analysis methods including survival analysis and multivariate analysis using Cox proportional hazards regression and investigated outcomes associated with both symptomatic UTIs (primary) and bacteriuria (secondary).

These results were confirmed by two additional RCTs. Linsenmeyer et al. (2004) found that cranberry tablets (400 mg) were not effective in changing bacterial or white blood cell (WBC) counts of 21 participants who underwent a 9 week placebo-controlled, crossover trial. Similar results were obtained by Waites et al. (2004) in community residing persons with SCI of greater than 1 years duration (n=48) which showed no difference between cranberry extract or placebo taken for 6 months in reducing bacteriuria or pyuria nor for reducing symptomatic UTI rates.

In contrast to these findings, a prospective controlled trial (n=15) conducted by Reid et al. (2001) showed that cranberry juice intake significantly reduced the adhesion of bacteria to bladder cells whereas water intake did not significantly reduce the bacterial adhesion or biofilm presence in individuals with SCI. These conflicting conclusions may be influenced by the variation in “dose” and formulation of cranberry product (i.e., tablet vs juice) and the outcome measures used across the various studies. Notably, this study (Reid et al. 2001) was not designed or intended to assess the effect of cranberry on asymptomatic UTI.

Hess et al. (2008) comment in their discussion that subjects in the Waites study may have been non-compliant given that study medication was mailed to subjects, that the UTI definition may not have been as robust, and that there was an imbalance in bladder management methods between groups. It is important to be note that Hess, Linsenmeyer, and Waites lack intent-to-treat statistical analyses which therefore reduces the quality of these investigations. The lack of consistency between results underscores the need for yet further efforts to convincingly prove or disprove the potential value of cranberry prophylaxis.

Conclusion

There is conflicting level 1 evidence across 4 RCTs (1 +ive, 3 –ive) to support the effectiveness of cranberry in preventing UTI in patients with neurogenic bladder due to SCI.

  • It is uncertain if cranberry is effective in preventing UTIs in persons with SCI.

Educational Interventions for Maintaining a Healthy Bladder and Preventing UTIs

SCI patients with neurogenic bladder typically receive education while in initial rehabilitation to assist with bladder management and maintain a healthy bladder. This may continue as their bladder function changes following rehabilitation discharge.

Table: Individual Studies of Educational Interventions

Discussion

Health care providers have an excellent opportunity to provide proper bladder management education during inpatient rehabilitation to significantly affect the quality of bladder management after discharge with the goal of assisting clients in maintaining a healthy bladder, often manifest through prevention of UTIs. Anderson et al. (1983) reported on a case-control study where patients completed a special urinary tract care education program consisting of classes, reading material, written examinations, and demonstration of acquired skills. With this approach 71% of patients were asymptomatic of UTI at 6 month follow-up. Only 32% of patients had no symptoms when a group of patients, tested 4 years earlier in 1975, did not undergo the education program. Furthermore, as a result of the education program only 5% of the educated group lost time from their usual daily activities compared to 23% of the non-educated group losing time. However, both groups registered the same incidence of confirmed or suspected UTI (62-63%). Therefore, the benefit translated into early detection and definitive action resulting in less impairment and less lost time due to the UTI. This study was assessed as comprising Level 4 evidence due to inadequate control of potential confounds between the education and non-education group among other limitations.

Once discharged, some SCI patients experience unacceptable recurrence of UTIs. Cardenas et al. (2004) examined the effectiveness of an educational program in an RCT of 56 community-dwelling SCI patients with a self-reported history of UTIs. The educational intervention included written material, a self-administered test, a review by nurse and physician, and a follow-up telephone call. The control group did not receive the intervention and final interventional data was compared to an equivalent baseline period. A significant decrease in urine bacterial colony count (but not in UTI incidence) and increased Multidimensional Health Locus of Control scale score reflected the beneficial effects of UTI educational intervention in improving bladder health and the patient’s perception of control over their own health behaviour.

These results were amplified by Hagglund et al. (2005) and Barber et al. (1999), who each examined participants with longstanding SCI and conducted their investigations in conjunction with outpatient rehabilitation follow-up services. Positive benefits of reduced UTI occurrences were seen following a 6 hour physician-mediated educational workshop conducted as part of a prospective controlled trial with 6 month follow-up periods (n=60) (Hagglund et al. 2005). Of note, Hagglund et al. (2005) directed their educational intervention at the consumer-personal assistant dyad.

Barber et al. (1999) identified 17 high risk patients (i.e., ≥ 2 UTI/6months) over 1000 consecutive outpatient SCI clinic days. These authors found that 11 (65%) of these patients were able to reduce their number of UTIs to be reclassified as not high-risk with intensive counseling on proper bladder management technique and hygiene, although 8 required multiple counseling sessions to realize an effective reduction of number of UTIs. The remaining patients in this series required pharmaceutical prophylaxis for UTI prevention although there were some issues with compliance when treatment was extended over 1 year. The authors suggested that education intervention by a clinic nurse is a simple, cost-effective means of decreasing the risk of UTIs in at-risk SCI individuals, although the sample size was small and the study was neither randomized nor controlled.

Conclusion

  • There is level 1 evidence from a single RCT that a single educational session conducted by SCI specialist health professionals with accompanying written materials and a single follow-up telephone call can result in reduced urine bacterial colony counts in community-dwelling individuals with prior history of SCI.
  • The beneficial effects of education mediated by SCI specialist health professionals on reducing UTI risk in community-dwelling individuals with SCI are supported by a single level 2 study and two level 4 studies incorporating different features such as one-on one or group workshops, demonstrations, practice of techniques and written materials.
  • There is no evidence assessing the relative effectiveness of different educational approaches for reducing UTI risk. 
  • A variety of bladder management education programs are effective in reducing UTI risk in community-dwelling persons with SCI, although limited information exists as to the most effective approaches.

Pharmacological Treatment of UTIs

UTIs in persons with SCI with neurogenic bladder are termed “complicated UTIs” which refers to the presence of a UTI in a functionally, metabolically, or anatomically abnormal urinary tract or that are caused by pathogens that are resistant to antibiotics (Stamm & Hooton 1993). Complicated UTIs may be caused by a much wider variety of pathogens in persons with SCI and are often polymicrobial. It is generally recommended that persons with SCI be treated for bacteriuria only if they have symptoms, as many individuals especially with indwelling or suprapubic catheters typically have asymptomatic bacteriuria (Biering-Sorensen et al. 2001). Once symptomatic UTI is confirmed, the first line of empirical treatment is via antibiotics and the most common antibiotics chosen for UTI treatment include fluorquinolones (e.g. ciprofloxacin), trimethorprin, sufamethoxazole, amoxicillin, nitrofurantoin and ampicillin. Fluorquinolones are often chosen because of their effectiveness over a wide spectrum of bacterial strains (Waites et al. 1991; Garcia Leoni & Esclarin De Ruz 2003). Although much experience with treating UTIs in SCI has been gleaned from other indications, there are several studies that are reviewed below which have investigated a variety of antibiotic agents in this population.

Table: Antibiotics in Treatment of UTIs

Discussion

The range of effective antibiotic treatment duration can vary widely depending on the specific microorganism causing the infection, the antibiotic used and the patients’ UTI history. Dow et al. (2004) conducted a RCT (n=60) to compare a 14 vs 3 day course of ciprofloxin treatment in SCI patients with UTI symptoms or microbially documented bacteriuria and concluded that a 14 day Ciprofloxin treatment results in improved clinical and microbiological outcomes.  Microbiological relapse rates were significantly lower for those patients treated for 14 vs 3 days. Although, this high quality level 1 evidence advocates for the use of a 14 vs 3 day course of ciprofloxacin in SCI UTI, as the author notes, it does not address the optimal treatment period which may be 5, 7 or 10 days nor does it examine the question of whether a higher dose might have been more effective with the shorter therapy.

Ofloxacin is a fluoroquinolone antibiotic shown to be promising in its ability to penetrate and eradicate bacterial biofilms in the bladder in vitro and in SCIpatients (Reid et al. 1994a; Reid et al. 1994b). Bacterial biofilms are colonies of microorganisms along with their extracellular products that may form on surfaces as a structured community that enables the pathogens to resist antibiotics and persist in the urinary tract thereby potentially causing recurrent UTI (Biering-Sorensen et al. 2003). Reid et al. (2000) employed a randomized, double blind design (n=42) to assess the relative effectiveness of a 7 day course of ofloxacin as compared to trimethoprim-sulphamethoxazole (TMP-SMX) or other more appropriate antibiotics as detected by culture sensitivity. Study participants had symptomatic UTI and clinical cure rates, defined as patients becoming asymptomatic with sterile urine, were assessed at day 4 and day 7. Clinical cure rate was significantly greater for Ofloxacin as compared to TMP-SMX or other antibiotic at day 4 (90% vs 48%, p=0.003) and day 7 (90% vs 57%, p=0.015). In addition, both treatments were effective at reducing bacterial biofilms at day 4 and 7 (p<.001) although the biofilm eradication rate was significantly higher with Ofloxacin vs TMP-SMX or other antibiotic at day 4 (62% vs 24%, p=.005); and day 7 (67% vs 35%, p=.014). This finding was supported by an earlier study (Reid et al. 1994a) noting that fluoroquinolone therapy was more effective at reducing bladder cell adhesion counts in 63% of asymptomatic SCI UTIs vs 44% of SCI subjects treated with trimethoprim-sulfamethoxazole.    

Reid et al. (2000) suggested that a 3-day regimen in the treatment of SCI UTI could be sufficient based on significant biofilm eradication detected in bladder epithelial cells in patients treated with Ofloxacin compared to TMP-SMX. Shorter courses of antibiotic treatment are currently considered by clinicians and patients who are concerned with side effects, cost and antimicrobial resistance due to longer term use. Treatment course durations as short 3 days are not uncommon while the more common treatment duration is 14 days. The difference in effective treatment duration, compared to the findings of Dow et al. (2004), is due, in part, to the difference in anti-microbial used. However, further study comparing the 2 antimicrobials (and others) and differing treatment durations are required to clarify the question of optimum treatment duration for the antimicrobial being considered for use.

Gram-negative bacteria such as Pseudomonas, Acinetobacter, Enterobacter and mycobacteria are susceptible to aminoglycosides such as tobramycin and amikacin which may be chosen for complicated UTI treatment. Due to their toxicity and inconvenient route of administration (i.e. intramuscular injection), their use is limited. To investigate the effectiveness of a lower dose of these aminoglycosides, Sapico et al. (1980) compared infection, persistence and reinfection rates of SCI UTI against a standard dose. An overall low rate of success and no differences between the dose strengths and between tobramycin and amikacin even though high antibiotic concentrations were found in the urine of all subjects suggested that alternative antimicrobial agents would be better to consider for use in this population.

Although Waites et al. (1991) showed norfloxacin, another fluoroquinolone, to be 73% effective in eradicating UTIs by mid-treatment, the rate of reinfection was 84% after 8 to 12 weeks post initial eradication. Furthermore, 16% of strains isolated after eradication became resistant to norfloxacin. This trial, employing a pre-post study design (n=78) with a 14 day course of treatment, enrolled participants with symptomatic UTI and the equivocal results point to the utility of controlled study designs when assessing antibiotic effectiveness. The authors concluded that norfloxacin is a reasonable treatment choice for SCI UTI but the subsequent and problematic emergence of resistance must be monitored (as with other antimicrobials).  

In addition to decisions on selecting the most appropriate antibiotic, the clinician is sometimes faced with additional treatment option challenges when multi-drug resistant bacteria or the patient’s allergy to the appropriate antibiotic are encountered. Although conflicting results have been obtained with the use of antiseptic agents as part of a prophylactic strategy to lower urine pH and thereby assist in the prevention of UTIs, Linsenmeyer et al. (1999) used a case series review (n=10) to investigate the use of medicated bladder irrigation as a method to alter the existing antimicrobial resistance. They found that intermittent neomycin/polymyxin bladder irrigation was effective in altering the resistance of the offending bladder organism(s) to allow for appropriate antibiotic treatment, therefore proving preliminary evidence advocating for a short course treatment of neomycin/polymyxin irrigant to alter existing antimicrobial resistance.

Conclusion

  • There is level 1 evidence from a single RCT that supports the use of 14 vs 3 days of Ciprofloxcin for improved clinical and microbiological outcomes in the treatment of UTI in persons with SCI.
  • There is level 1 evidence from a single RCT suggesting that 3 or 7 day Ofloxacin treatment is more effective than trimethoprim-sulfamethoxazole in treating UTI and results in significant bladder bacterial biofilm eradication in persons with SCI patients.
  • Level 4 evidence from a single study suggests that norfloxacin may be a reasonable treatment choice for UTI in SCI but subsequent resistance must be monitored.
  • A low success rate of aminoglycosides in the treatment of SCI UTI is supported by level 1 evidence from a single RCT.
  • Optimum antimicrobial treatment duration and dosage is uncertain due to the lack of comparative trials in persons with SCI.
  • Level 4 evidence is reported for intermittent neomycin/polymyxin bladder irrigation being effective in altering the resistance of the offending bladder organism(s) to allow for appropriate antibiotic treatment.
  • Ciprofloxin administered over 14 (vs 3) days may result in improved clinical and microbiological SCI UTI treatment outcome.

    Ofloxacin administered over either a 3 or 7 day treatment regimen may result in significant SCI UTI cure and bladder bacterial biofilm eradication rate, moreso than trimethoprim-sulfamethoxazole.

    Norfloxacin may be a reasonable treatment choice for UTI in SCI but
    subsequent resistance must be monitored.

    Aminoglycosides have a low success rate in the treatment of SCI UTI.

    Intermittent neomycin/polymyxin bladder irrigation may be effective in altering the resistance of the offending bladder organism(s) to allow for appropriate antibiotic treatment.

Summary

  • Level 1 evidence from two RCTs supports the use of propiverine in the treatment of detrusor hyperreflexia resulting in significantly improved bladder capacity, with one of these trials showing equivalent results to oxybutinin but fewer side effects, notably dry mouth.

    Level 1 evidence from a single RCT supports the use of tolterodine vs placebo to significantly increase intermittent catheterization volumes and decrease incontinence in neurogenic detrusor overactivity.

    Level 2 evidence from a small single open label prospective controlled trial that tolterodine and oxybutynin are equally efficacious in SCI patients with neurogenic detrusor overactivity except that tolterodine results in less dry mouth.

    Level 4 evidence from single pre-post trials support the potential benefits of controlled-release oxybutynin as well as a transdermal system for oxybutinin administration, the latter with reduced side effect profile.

    Level 4 evidence from a single study suggests benefits such as reduced incontinence and increased bladder capacity from combination treatments of two of oxybutinin, trospium or tolterodine, even in patients with unsatisfactory outcomes following a trial with one of these medications.

    Level 1 evidence from a single RCT supports the use of trospium chloride to increase bladder capacity and compliance, and decrease bladder pressure with very few side effects in SCI individuals with neurogenic bladder.

    Level 1 evidence based on two RCTs supports the use of Onabotulinum toxin A injections into the detrusor muscle to provide targeted treatment for neurogenic detrusor overactivity and urge incontinence resistant to high-dose oral anticholinergic treatments with intermittent self-catheterization in SCI. Numerous level 3 and 4 studies confirm the efficacy and safety.

    Level 4 evidence based on a single case series indicates detrusor contractility may be decreased through repeated BoNT-A injection, though prospective study and higher levels of evidence is needed to confirm.

    Level 1 evidence supports the use of vanillanoid compounds such as capsaicin or resiniferatoxin to increase maximum bladder capacity and decrease urinary frequency and leakages in neurogenic detrusor overactivity of spinal origin.

    Level 4 evidence exists to suggest that intravesical capsaicin instillation in bladders of SCI individuals does not increase the rate of common bladder cancers after 5 years of use.

    Level 1 evidence based on two small-scale RCTs supports the use of N/OFG, a nociceptin orphan peptide receptor agonist for the treatment of neurogenic bladder in SCI.

    There is level 4 evidence from 3 studies that instillations with oxybutinun or propantheline have equivocal benefits for neurogenic bladder in people with SCI. There is level 4 evidence from1 study that combined oral and intravesical installation of oxybutinin significantly improves bladder volume. There is level 4 evidence suggesting systemic absorption may occur with this therapy, resulting in systemic side effects.

    There is level 1 evidence from a single small RCT (n=10) that intrathecal baclofen may be beneficial for bladder function improvement in individuals with SCI when oral pharmacological interventions are insufficient.

    Level 4 evidence is available from a single, small (n=9), case series study for the use of intra-thecal clonidine to improve detrusor overactivity in individuals with SCI when a combination of oral treatment and sterile intermittent catheterization are insufficient.

    There is level 4 evidence from four studies that surgical augmentation of bladder (ileocystoplasty) may result in enhanced bladder capacity under lower filling pressure and improved continence in persons with SCI who previously did not respond well to conservative approaches for overactive bladder.

    There is level 3 evidence from a single study that extraperitoneal (vs intraperitoneal) augmentation enterocystoplasty produces equivocal postoperative continence with easier early postoperative recovery.

    Level 1 evidence from a single study suggests that moxisylyte decreases maximum urethral closure pressure by 47.6% at 10 minutes after an optimum dose of 0.75mg/kg in individuals with SCI.

    There is level 4 evidence from a single study that suggests that tamsulosin may improve bladder neck relaxation and subsequent urine flow in SCI individuals.

    There is level 4 evidence (two studies, n=28 & 9) that supports terazosin as an alternative treatment for bladder neck dysfunction in SCI individuals provided that side effects and drug tolerance are monitored.

    There is level 4 evidence derived from a single, case series study involving 46 subjects (41 completers) that indicates some potential for phenoxybenzamine as an adjunct treatment for neurogenic bladder following SCI, when tapping or crede is insufficient to achieve residual urine volume of <100mL. Further evidence is required.

    Level 4 evidence from 1 small retrospective chart review suggests that 6 months of alpha 1-blocker therapy may improve upper tract stasis secondary to SCI in men by decreasing the duration of involuntary bladder contractions.

    There is level 1 evidence from a single RCT with support from several additional controlled and uncontrolled trials that botulinum toxin injected into the external urinary sphincter may be effective in improving outcomes associated with bladder emptying in persons with neurogenic bladder due to SCI.

    There is level 4 evidence from a single study that PDE5 inhibitors may be effective in improving outcomes associated with bladder emptying in persons with neurogenic bladder due to SCI.

    There is level 4 evidence from a single study that 4-aminopyridine, at sufficient dosage, may be effective in restoring sensation and/ or control of the bladder sphincter.

    There is level 4 evidence that indwelling urethral catheterization is associated with a higher rate of acute urological complications than intermittent catheterization.

    There is level 4 evidence that prolonged indwelling catheterization, whether suprapubic or urethral, may result in a higher long-term rate of urological and renal complications than intermittent catheterization, condom catheterization or triggered spontaneous voiding.

    There is level 4 evidence that intermittent catheterization, whether performed acutely or chronically, has the lowest complication rate.

    Results are conflicting about the complications associated with chronic use of spontaneous triggered voiding but some authors present level 4 evidence that this method has comparable long-term complication rates to intermittent catheterization.

    There is level 4 evidence that those who use intermittent catheterization at discharge from rehabilitation may have difficulty continuing, especially those with tetraplegia and complete injuries. Females also have more difficulty than males in maintaining compliance with IC procedures.

    There is Level 1 evidence based on 1 RCT that pre-lubricated hydrophilic catheters are associated with fewer UTIs and reduced incidence of urethral bleeding and microtrauma as compared to conventional Poly Vinyl Chloride catheters.

    There is Level 2 evidence based on 1 lower quality RCT that fewer UTIs, but not necessarily urethral bleeding may result with the use of hydrophilic catheters as compared to conventional PVC catheters.

    There is Level 2 evidence based on 1 lower quality RCT that urethral microtrauma and pyuria is reduced with use of gel-lubricated non-hydrophilic catheter, with higher patient satisfaction, as compared to hydrophilic-coated or PVC catheters

    There is level 4 evidence that urethral complications and epididymoorchitis occurs more frequently in those using IC programs for bladder emptying, but the advantages of improved upper tract outcome over those with indwelling catheters outweigh these disadvantages.

    There is level 4 evidence that using a portable ultrasound device reduces the frequency and cost of intermittent catheterizations.

    There is level 4 evidence that triggering mechanisms such as the Valsalva or Crede maneuvers may assist some individuals with neurogenic bladder in emptying their bladders without catheterization. However, high intra-vesical voiding pressures can occur which could conceivably lead to renal complications.

    There is level 4 evidence, despite an associated significant incidence of urological and renal complications, acute and chronic indwelling suprapubic catheterization may still be a reasonable choice for bladder management for people with poor hand function, lack of care-giver assistance, severe lower limb spasticity, urethral disease, and persistent incontinence with urethral catheterization.

    There is level 4 evidence that those with indwelling catheters are at higher risk for bladder cancer compared to those with non-indwelling catheter management programs. Screening for cancer may require routine biopsy as well as cytoscopy.

    There is level 4 evidence that condom drainage may be associated with urinary tract infection and upper tract deterioration.

    There is level 4 evidence that penile implants may allow easier use of condom catheters, thereby reducing incontinence and improving sexual function.

    There is level 4 evidence that most individuals who receive catheterizable stomas become newly continent and can self-catheterize. It appears possible that this surgical intervention could protect upper tract function. Larger studies are needed to better evaluate true incidence of complications, and long-term bladder and renal outcome.

    There is level 4 evidence that most individuals undergoing cutaneous ileal conduit (ileo-ureterostomy) diversion became newly continent and were more satisfied than with their previous bladder management method. Long-term follow-up demonstrated the presence of a high incidence of urological or renal complications.

    There is level 4 evidence from eight studies and level 5 evidence from a single study that ongoing use of sacral anterior root stimulation (accompanied in most cases by posterior sacral rhizotomy) is an effective method of bladder emptying resulting in reduced incontinence for the majority of those implanted. This is associated with increased bladder capacity and reduced post-void residual volume.

    There is level 4 evidence from five studies and level 5 evidence from a single study (UTIs only) that sacral anterior root stimulation (accompanied in most cases by posterior sacral rhizotomy) may be associated with reducing UTIs and autonomic dysreflexia.

    There is level 4 evidence from two studies that direct bladder stimulation may result in reduced incontinence, increased bladder capacity and reduced residual volumes but requires further study as to its potential clinical use.

    There is level 4 evidence from various single studies that other forms of neuroanatomically-related stimulation (e.g., electrical conditioning stimulation to posterior sacral, pudenal, dorsal penile or clitoral nerve or surface magnetic sacral stimulation) may result in increased bladder capacity but require further study as to their potential clinical use. Further development involving some of these approaches may permit sacral anterior root stimulation without the need for posterior root ablation.

    There is limited level 2 evidence from a single small study that reports early sacral neuromodulation may improve management of lower urinary tract dysfunction. Further investigation is required to confirm the results and substantiate the hypothesis of resultant plastic changes of the brain.

    There is level 4 evidence from a single study that epidural dorsal spinal cord stimulation at T1 or T11 originally intended for reducing muscle spasticity may have little effect on bladder function.

    There is level 4 evidence from a single study that a program of functional electrical stimulation exercise involving the quadriceps muscle originally intended for enhancing muscle function and reducing muscle spasticity has only marginal (if any) effects on bladder function.

    There is level 4 evidence from a single case-series study that sphincterotomy is effective in reducing episodes of autonomic dysreflexia associated with inadequate voiding.

    There is level 4 evidence from a single case-series study that sphincterotomy, as a staged intervention, can provide long-term satisfactory bladder function.

    There is level 2 evidence from a single low-quality RCT but supported by level 4 studies that both sphincterotomy and implantation of a sphincteric stent are effective in reducing incontinence, with little need for subsequent catheterization, and both treatments are associated with reduced detrusor pressure and reduced post-void residual volume but not with changes in bladder capacity. The only significant difference in these 2 treatments was the reduced initial hospitalization associated with the stent, given the lesser degree of invasiveness.

    There is level 4 evidence that implantation of a sphincteric stent may result in reduced incidence of UTIs and bladder-related autonomic dysreflexia over the short-term although several studies have demonstrated the potential for various complications and subsequent need for re-insertion or another approach over the long-term.

    There is level 4 evidence from a single long-term follow-up study of those having a previous sphincterotomy that the incidence of various upper and lower tract urological complications may be quite high.

    There is level 4 evidence from a single case-series study that advocates for placement of a temporary stent early after injury as a reversible option that allows patients to choose from the range of permanent stent placement to less invasive bladder management methods such as intermittent catheterization.

    There is level 4 evidence based on a single study that transurethral balloon dilation of the external sphincter may permit removal of indwelling catheters in place of condom drainage, and also may result in reduced detrusor pressure and post-void residual volume but not with changes in bladder capacity.

    There is level 4 evidence based on 2 studies that implantation of an artificial urinary sphincter may be useful in the treatment of incontinence in SCI but further study is required.

    There is level 4 evidence from a single pre-post study that transurethral incision of the bladder neck may be useful in bladder neck and voiding dysfunction.

    There is level 2 evidence from a single study that early treatment with electroacupuncture may shorten the time that it takes to develop low pressure voiding /emptying with minimal residual volume, when combined with conventional methods of bladder management.

    Level 4 evidence from two studies suggests that intranasal DDVAP may reduce nocturnal urine production with fewer night-time emissions and also may reduce the need for more frequent catheterizations in persons with SCI with neurogenic bladder that is otherwise unresponsive to conventional therapy.

    There is level 4 evidence from four studies that nerve crossover surgery (anastomosis of more rostral ventral nerve roots to S2-S3 spinal nerve roots) may result in improved bladder function in chronic SCI.

    Level 1 evidence based on a single RCTon SCI inpatients suggests that both limited and full microbial investigation result in adequate clinical response to UTI treatment with antibiotics. Therefore the cost savings attributed to a limited microbial investigation favours this practice in the investigation of UTI although more rigorous investigation of the patient outcomes and attributed costs is needed.

    There is limited level 1 evidence from a single investigation that refrigeration (up to 24 hours) of urine samples prior to sample processing does not significantly alter urinalysis or urine culture results in SCI patients.

    There is limited level 2 evidence from a single investigation that fewer false positive tests showing bacteriuria occur if indwelling or suprapubic catheters are changed prior to collection for urine culture analysis.

    There is conflicting level 4 evidence from two investigations concerning whether dipstick testing for nitrates or leukocyte esterase is recommended to guide treatment decision-making.

    Level 2 evidence based on two RCTs suggests no difference in UTI rates between sterile vs clean approaches to intermittent catheterization during inpatient rehabilitation, however, using a sterile method is significantly more costly.

    There is limited level 4 evidence from a single study that there is no difference in UTI rates between intermittent catheterization conducted by the patients themselves or by a specialized team during inpatient rehabilitation.

    There is limited level 4 evidence from a single study that similar rates of UTI may be seen for those using clean intermittent catheterization during inpatient rehabilitation as compared to those using similar technique over a much longer time when living in the community.

    There is limited level 4 evidence from a single study that differences in residual urine volume ranging from 0-153 ml were not associated with differences in UTI during inpatient rehabilitation.

    There is level 1 evidence based on 1 RCT that pre-lubricated nonhydrophilic catheters are associated with fewer UTIs as compared to conventional Poly Vinyl Chloride catheters.

    There is conflicting level 2 evidence based on 1 RCT that fewer UTIs may result with the use of hydrophilic catheters as compared to conventional PVC catheters.

    There is level 2 evidence based on 2 RCTs that use of hydrophilic vs non-hydrophilic catheters are associated with fewer symptomatic UTIs treated with antibiotics even though the number of symptomatic UTIs are similar between groups.

    There is level 2 evidence based on a single prospective controlled trial and supported by a case control study that intermittent catheterization may lead to a lower rate of UTI as compared to other bladder management techniques such as use of indwelling or suprapubic catheter.

    There is level 3 evidence based on a single case control study that bladder management with a suprapubic as opposed to indwelling catheter may lead to a lower rate of UTI and reduced mortality in a poor, illiterate population where intermittent catheterization may not be viable as an approach to bladder management.

    There is weak level 2 evidence based on a single low quality RCT that suggests that use of the Statlock device to secure indwelling and suprapubic catheters may lead to a lower rate of UTI.

    There is level 2 evidence based on a single prospective controlled trial that suggests that removal of external condom drainage collection systems at night or for 24 hours/day might reduce perineal, urethral or rectal bacterial levels but have no effect on bacteriuria.

    There is level 4 evidence based on a single case series that no bladder management method is advantageous in preventing pyelonephritis (though indwelling urethral catheterization does have the highest incidence of upper tract deterioration). However, the presence of reflux results in a 2.8 fold higher incidence of pyelonephritis.

    There is level 1 evidence based on a single RCT and supported by two level 4 investigations that bacterial interference in the form of E. coli 83972 bladder inoculation may prevent UTIs.

    There is level 1 evidence from a single RCT that low-dose, long-term ciprofloxacin may prevent symptomatic UTI.

    There is level 1 evidence from a single RCT that TMP-SMX as prophylaxis may reduce symptomatic UTI rates although conflicting findings were obtained from 2 prospective controlled trials. The potential for emergence of drug resistant bacteria and TMP-SMX related adverse events further limit the potential use of TMP-SMX for prophylaxis.

    There is level 4 evidence from a single study that suggests weekly oral cyclic antibiotic use, customized as to individual allergy and antimicrobial susceptibility, may be effective for UTI prevention in SCI patients, and UTI reduction in pregnant patients.

    There is level 1 evidence based on a single RCT that oral methenamine hippurate, either alone or in combination with cranberry, is not effective for UTI prevention.

    There is level 2 evidence from separate studies that bladder irrigation with trisdine, kanamycin-colistin or a 5% hemiacidrin solution combined with oral methenamine mandelate (2 mg qid) may be effective for UTI prevention.

    There are varying levels of evidence that bladder irrigation with neomycin/polymyxin (level 1), acetic acid (level 1), ascorbic acid (level 2) or phosphate supplementation (level 4) is not effective for UTI prevention.

    There is level 2 evidence based on a single low quality RCT that supports the use of daily body washing with chlorohexidine and application of chlorhexidine cream to the penis after every catheterization versus using standard soap to reduce bacteriuria and perineal colonization.

    There is conflicting level 1 evidence across 4 RCTs (1 +ive, 3 –ive) to support the effectiveness of cranberry in preventing UTI in patients with neurogenic bladder due to SCI.

    There is level 1 evidence from a single RCT that a single educational session conducted by SCI specialist health professionals with accompanying written materials and a single follow-up telephone call can result in reduced urine bacterial colony counts in community-dwelling individuals with prior history of SCI.

    The beneficial effects of education mediated by SCI specialist health professionals on reducing UTI risk in community-dwelling individuals with SCI are supported by a single level 2 study and two level 4 studies incorporating different features such as one-on one or group workshops, demonstrations, practice of techniques and written materials.

    There is no evidence assessing the relative effectiveness of different educational approaches for reducing UTI risk.

    There is level 1 evidence from a single RCT that supports the use of 14 vs 3 days of Ciprofloxcin for improved clinical and microbiological outcomes in the treatment of UTI in persons with SCI.

    There is level 1 evidence from a single RCT suggesting that 3 or 7 day Ofloxacin treatment is more effective than trimethoprim-sulfamethoxazole in treating UTI and results in significant bladder bacterial biofilm eradication in persons with SCI patients.

    Level 4 evidence from a single study suggests that norfloxacin may be a reasonable treatment choice for UTI in SCI but subsequent resistance must be monitored.

    A low success rate of aminoglycosides in the treatment of SCI UTI is supported by level 1 evidence from a single RCT.

    Optimum antimicrobial treatment duration and dosage is uncertain due to the lack of comparative trials in persons with SCI.

    Level 4 evidence is reported for intermittent neomycin/polymyxin bladder irrigation being effective in altering the resistance of the offending bladder organism(s) to allow for appropriate antibiotic treatment.

Key Points

DESD Therapy in SCI: Enhancing Bladder Volumes Pharmacologically

Anticholinergic Therapy for SCI-Related Detrusor Overactivity

Propiverine, oxybutynin, tolterodine and trospium chloride are efficacious anticholinergic agents for the treatment of SCI neurogenic bladder.

  • Treatment with 2 of oxybutynin, tolterodine or trospium may be effective for the treatment of SCI neurogenic bladder in those not previously responding to one of these medications.
  • Tolterodine, propiverine, or transdermal application of oxybutinin likely result in less dry mouth but are similarly efficacious to oral oxybutynin in terms of improving neurogenic detrusor overactivity.

Intravesical Instillations for SCI-Related Detrusor Overactivity

  • Intravesical instillations with oxybutinun or propantheline alone are ineffective for treating neurogenic bladder in people with SCI.

Other Pharmaceutical Treatments for SCI-Related Detrusor Overactivity

  • Intrathecal baclofen and clonidine may be beneficial for bladder function improvement but further confirmatory evidence is needed.

 

DESD Therapy in SCI: Enhancing Bladder Volumes Non-Pharmacologically

Surgical Augmentation of the Baldder to Enhance Volume

  • Surgical augmentation of bladder may result in enhanced bladder capacity under lower filling pressure and improved continence in persons with SCI.
  • Extraperitoneal vs intraperitoneal augmentation enterocystoplasty may result in better postoperative recovery.

 

DESD Therapy in SCI: Enhancing Bladder Emptying Pharmacologically

Alpha-adrenergic Blockers for Bladder Emptying

  • Tamsulosin may improve urine flow in SCI individuals with bladder neck dysfunction.
  • Mosixylyte is likely able to decrease maximum urethral closure pressure at a dose of 0.75mg/kg in individuals with SCI.
  • Terazosin may be an alternative treatment for bladder neck dysfunction in individuals with SCI but side effects and drug tolerance should be monitored.
  • Phenoxybenzamine may be useful as an adjunct therapy for reducing residual urine volume in SCI neuropathic bladders maintained by crede or tapping.
  •  months of alpha 1-blocker therapy in male SCI patients may improve upper tract stasis.

Botulinum Toxin for Bladder Emptying

  • Botulinum toxin injected into the sphincter is effective in assisting with bladder emptying for persons with neurogenic bladder due to SCI.

Other Pharmaceutical Treatments for Bladder Emptying

  • A single dose of oral tadalafil is effective in improving urodynamic indices in males with supra sacral SCI; more evidence is needed to support this as a treatment option.
  • 4-Aminopyridine at sufficient dosage may return sensation and control of the bladder sphincter following SCI; more evidence is needed to support this as a treatment option.

 

DESD Therapy in SCI: Enhancing Bladder Emptying Non-Pharmacologically

Comparing Methods of Conservative Bladder Emptying

  • Intermittent catheterization, whether performed acutely or chronically, has the lowest complication rate.
  • Indwelling catheterization, whether suprapubic or urethral or whether conducted acutely or chronically, may result in a higher long-term rate of urological and renal complications than other management methods.
  • Persons with tetraplegia and complete injuries, and to a lesser degree females, may have difficulty in maintaining compliance with intermittent catheterization procedures following discharge from rehabilitation.
  • Intermediate Catheterization
  • Although both pre-lubricated and hydrophilic catheters have been associated with reduced incidence of UTIs as compared to conventional Poly Vinyl Chloride catheters, less urethral microtrauma with their use may only be seen with pre-lubricated catheters.
  • Urethral complications and epididymoorchitis occur more frequently in those using intermittent catheterization programs.
  • Portable ultrasound device can improve the scheduling of intermittent catheterizations.

Triggering-Type of Expression Voiding Methods of Bladder Management

  • Valsalva or Crede maneuver may assist some individuals to void spontaneously but produce high intra-vesical pressure, increasing the risk for long-term complications.

Indwelling Catheterization (Indwelling or Suprapubic)

  • With diligent care and ongoing medical follow-up, indwelling suprapubic catheterization may be an effective and satisfactory bladder management choice for some people, though there is insufficient evidence to report lifelong safety of such a regimen
  • Indwelling catheter users are at higher risk of bladder cancer, especially in the second decade of use, though risk also increases during the first decade of use.

Condom Catheterization

  • Patients using condom drainage should be monitored for complete emptying and for low pressure drainage, to reduce UTI and upper tract deterioration. Sphincterotomy may eventually be required.
  • Penile implants may allow easier use of condom catheters and reduce incontinence.
  • Continent Catheterizable Stoma and Incontinent Urinary Diversion
  • Catheterizable abdominal stomas may increase the likelihood of achieving continence and independence in self-catherization, and may result in a bladder management program that offers more optimal upper tract protection.
  • Cutaneous ileal conduit diversion may increase the likelihood of achieving continence but may also be associated with a high incidence of various long-term complications.

Electrical Stimulation for Bladder Emptying (and Enhancing Volumes)

  • Sacral anterior root stimulation (accompanied in most cases by posterior sacral rhizotomy) enhances bladder function and is an effective bladder management technique though the program (surgery and followup) requires significant expertise.
  • Direct bladder stimulation may be effective in reducing incontinence and increasing bladder capacity but requires further study.
  • Posterior sacral, pudenal,dorsal penile or clitoral nerve stimulation may be effective to increase bladder capacity but requires further study.
  • Early sacral neural modulation may improve management of lower urinary tract dysfunction but requires further study.

Sphincterotomy, Artificial Sphincter, Stents and Related Approaches for Bladder Emptying

  • Surgical and prosthetic approaches (with a sphincterotomy and stent respectively) to allow bladder emptying through a previously dysfunctional external sphincter both seem equally effective resulting in enhanced drainage although both may result in long-term upper and lower urinary tract complications.
  • Artificial urinary sphincter implantation and transurethral balloon dilation of the external sphincter may be associated with improved bladder outcomes but require further study.

 

DESD Therapy in SCI: Other Miscellaneous Treatments

  • Early electroacupuncture therapy as adjunctive therapy may result in decreased time to achieve desired outcomes.
  • Intranasal DDVAP may reduce nocturnal urine emissions and decrease the frequency of voids (or catheterizations).
  • Anastomosis of the T11, L5 or S1 to the S2-S3 spinal nerve roots may result in improved bladder function in chronic SCI.

 

Urinary Tract Infections: Detecting and Investigating UTIs

  • Both limited and full microbial investigation may result in adequate clinical response to UTI treatment with antibiotics.
  • Indwelling or suprapubic catheters should be changed just prior to urine collection so as to limit the amount of false positive urine tests.
  • Urinalysis and urine culture results of SCI patients are not likely to be affected by sample
  • refrigeration (up to 24 hours).
  • It is uncertain if dipstick testing for nitrates or leukocyte esterase is useful in screening for bacteriuria to assist treatment decision-making.

 

Urinary Tract Infections: Non-Pharmacological Methods of Preventing UTIs

Intermittent Catheterization NS Prevention of UTIs

  • Sterile and clean approaches to intermittent catheterization seem equally effective in minimizing UTIs in inpatient rehabilitation.
  • Similar rates of UTI may be seen with intermittent catheterization as conducted by the patients themselves or by a specialized team during inpatient rehabilitation.
  • Similar rates of UTI may be seen with intermittent catheterization, whether conducted in the short-term during inpatient rehabilitation or in the long-term while living in the community.
  • UTIs were not associated with differences in residual urine volumes after intermittent catheterization.

Intermittent Catheterization using Specially Coated Catheters for Preventing UTIs

  • A reduced incidence of UTIs or reduced antibiotic treatment of symptomatic UTIs have been associated with pre-lubricated or hydrophilic catheters as compared to standard non-hydrophilic catheters.

Other Issues Associated with Bladder Management and UTI Prevention

  • Intermittent catheterization is associated with a lower rate of UTI as compared to use of indwelling or suprapubic catheter.
  • The Statlock device to secure indwelling and suprapubic catheters may lead to a lower rate of UTI.
  • Removal of external condom drainage collection systems at night or for 24 hours/day may reduce perineal, urethral or rectal bacterial levels but has no effect on bacteriuria.
  • The presence of vesicoureteral reflux likely has a greater impact on development of significant infections than the choice of bladder management.

 

Urinary Tract Infections: Pharmacological and Other Biological Methods of UTI Prevention

Bacterial Interferences for Prevention of UTIs

  • E. coli 83972 bladder inoculation may prevent UTIs.

Antibiotic Prophylaxis of UTIs

  • Ciprofloxacin may be indicated for UTI prophylaxis in SCI but further research is needed to support its use.
  • Long-term use of TMP-SMX is not recommended for sustained use as a suppressive therapy for UTI prevention.
  • A weekly oral cyclic antibiotic, customized to the individual, may be beneficial in preventing UTI in SCI.

Antiseptic and Related Approaches for Preventing UTIs

  • Oral methenamine hippurate, either alone or in combination with cranberry, is not effective for UTI prevention.
  • The antiseptic agents delivered via bladder irrigation (5% hemiacidrin solution combined with oral methenamine mandelate) may be effective for UTI prevention, whereas others are not (i.e., trisdine, kanamycin-colistin, neomycin/polymyxin, acetic acid, ascorbic acid and phosphate supplementation).
  • Daily body washing with chlorohexidine and application of chlorhexidine cream to the penis after every catheterization instead of using standard soap may reduce bacteriuria and perineal colonization.

Cranberry for Preventing UTIs

  • It is uncertain if cranberry is effective in preventing UTIs in persons with SCI.

Urinary Tract Infections: Educational Intervention for Maintaining a Healthy Bladder and Preventing UTIS

  • A variety of bladder management education programs are effective in reducing UTI risk in community-dwelling persons with SCI, although limited information exists as to the most effective approaches.

 

Urinary Tract Infections: Pharmacological Treatments of UTIs

Antibiotic in Treatments of UTIs

  • Ciprofloxin administered over 14 (vs 3) days may result in improved clinical and microbiological SCI UTI treatment outcome.
  • Ofloxacin administered over either a 3 or 7 day treatment regimen may result in significant SCI UTI cure and bladder bacterial biofilm eradication rate, moreso than trimethoprim-sulfamethoxazole.
  • Norfloxacin may be a reasonable treatment choice for UTI in SCI but  subsequent resistance must be monitored.
  • Aminoglycosides have a low success rate in the treatment of SCI UTI.
  • Intermittent neomycin/polymyxin bladder irrigation may be effective in altering the resistance of the offending bladder organism(s) to allow for appropriate antibiotic treatment.

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