Bladder Management

Hsieh J, McIntyre A, Iruthayarajah J, Loh E, Ethans K, Mehta S, Wolfe D, Teasell R. (2014). Bladder Management Following Spinal Cord Injury. In Eng JJ, Teasell RW, Miller WC, Wolfe DL, Townson AF, Hsieh JTC, Connolly SJ, Noonan VK, Loh E, McIntyre A, editors. Spinal Cord Injury Rehabilitation Evidence. Version 5.0: p 1-196.


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 smooth muscle) relaxation, at low pressures, until it is socially appropriate to void. In the uninjured state, as the relaxed bladder fills to approximately 250 mL to 300 mL, its stretching will signal the brain to coordinate volitional sphincter relaxation and detrusor contraction to empty the bladder in a low pressure, environment. This coordinated function is achieved by the pons micturition centre and timing is controlled by the frontal cortex. The ability to fill and empty the bladder under low pressure is of utmost importance in maintaining health of the kidneys, maintaining continence and preventing urinary tract infections (UTI).

After SCI, neural connectivity from the sacral region of the spinal cord to the pons and cortex are disrupted, hence the loss of coordinated bladder filling and emptying. Involuntary functions of the kidney filtering urine from the blood and of the ureters pushing urine into the bladder for storage will continue despite the SCI. However, various types of SCI can affect bladder function in different ways such as: sensing a full bladder, overactivity or underactivity of the detrusor muscle and/or external sphincter, and dys-coordination between the two structures in the process of urination, The spastic (reflex) bladder usually occurs with injuries of T12 and above while the areflexic (flaccid) bladder usually occurs in injuries below T12-L1 in the region of the spinal cord known as the cauda equina.The functional goal of bladder dysfunction management following SCI is to find a bladder emptying program that is specific to the individual and his/her activities of daily living. This is an important overall goal since no two injuries are equivocal and therefore management strategies will differ accordingly and over time. Clinically, bladder management goals include achieving regular bladder emptying and avoiding stasis; avoiding high filling and voiding pressures; maintaining continence and avoiding abnormal frequency and urgency; and preventing and treating complications such as UTI, autonomic dysreflexia (usually only in those with injuries at or above T6), reflux, stones, and strictures.

In the present chapter, the literature has been classified into sections pertaining to type of bladder dysfunction, that is, neurogenic overactivity (hypperreflexia) or areflexia, assessment, and then methods of pharmacological or non-pharmacological treatments and methods of management. Prevention of complications is discussed according to the type of bladder dysfunction and relevant management methods. The last section focuses on UTI prevention and treatment. 

Types of Bladder Dysfunction in SCI

 

There are two main types of neurogenic bladder dysfunction in SCI: 1) hyperreflexic bladder represented by overactive, reflexic or spastic detrusor muscle activity, usually associated with external sphincter dysynergia (Detrusor External Sphincter Dyssynergia, DESD); and 2) areflexic or flaccid bladder, represented by underactive detrusor activity. Occasionally, detrusor overactivity secondary to SCI is seen without associated sphincter dysynergia, but this can also result in difficulty with continence. Methods to improve continence in those with or without DESD are often similar and are addressed in the sections on enhancing bladder volumes in DESD.

Detrusor Overactivity Associated with External Sphincter Dyssynergia

Destrusor overactivity associated with external sphincter dyssynergia is a type of dysfunction seen in those with injuries of the spinal cord affecting the upper motor neurons. In these cases, the actions between the detrusor muscle and the external sphincter is caused by a disruption of the coordinated pathway from the spinal cord above the sacral levels to the pontine micturition centre. Both the detrusor muscle and the external sphincter are overactive due to lack of control and to descending inhibition from the pons and cortex. Instead of a coordinated detrusor muscle contraction and external sphincter relaxation, both contract reflexively when the bladder is stretched during filling. The detrusor muscle becomes overactive, reflexively contracting even with small volumes in the bladder. Detrusor muscle contraction against an overactive external sphincter that obstructs outward flow, results 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 typical of spinal lesions in the sacral levels of the cord, 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 urine stasis. The external sphincter tone also tends to be flaccid and that can cause incontinence with maneuvers contributing to increased intraabdominal pressure (e.g., “Valsalva” maneuvers) including external pressure, straining during transfers, coughing and sneezing. Internal sphincter tone may, however, be intact due to the higher origin of sympathetic innervation and this may contribute to incomplete emptying, even with externally applied suprapubic pressure.

Compared to DESD, patients with detrusor areflexia comprise a much smaller proportion of the SCI population. Thus, there is very little literature examining the effectiveness of interventions for this latter patient subpopulation (e.g., individuals with detrusor areflexia). The paucity of literature on detrusor areflexia is represented by some individual studies that address both types of bladder dysfunction. Conversely, the current literature more commonly addresses DESD and therefore management and treatment of individuals with DESD appears to be the focus of the review below.

Detrusor External Sphincter Dyssynergia Therapy in Spinal Cord Injury

Spinal cord injury commonly results in the loss of the coordinated relationship between the detrusor muscle of the bladder and the external urethral sphincter. Normally, filling of the bladder will result in autonomic (involuntary) contraction of the smooth muscle of the detrusor muscle (including the internal urethral sphincter). With SCI realted bladder dysfunction, instead of being able to voluntarily relax the skeletal muscle of the external urethral sphincter to allow voiding when the detrusor muscle contracts, the former contracts to seal off urine flow from the bladder. If this dyssynergia is not managed, the limited capacity of the bladder will result, in increased pressure within the bladder and, in back pressure and reflux into the ureters and kidneys. These conditions (i.e., increased intravesical pressure, vesicoureteric or vesicorenal reflux), if unmanaged, will ultimately lead to kidney damage (hydronephrosis). Other potential consequences include symptoms of overactive bladder (leaking, increased discomfort and urge incontinence, and nocturia), autonomic dysreflexia, UTI, pyelonephritis, calculi (renal and bladder) and ultimately kidney failure. To manage DESD, goals to reduce bladder outlet obstruction 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 (IC) 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 (sphincterotomy). Methods to enhance bladder volumes will be discussed first. Note that this pertains to people usually on concomitant IC 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 used 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 (TCL, 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 been tested in clinical trials for people with SCI and neurogenic detrusor overactivity (NDO). Only those that have been trialed for SCI-related neurogenic bladder are presented here.

Propiverine

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 15 mg thrice daily administration of propiverine over two weeks yielded significant improvement in 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 IC. Side effects (primarily dry mouth) were considered tolerable.

Two propiverine hydrochloride formulations, extended-release versus immediate-release (ER: 45 mg daily versus IR 15 mg thrice daily), proved to be equally effective in 65 people with SCI with proven NDO. This double-blind, randomized, multicenter study (Stohrer et al. 2013) also presented data to demonstrate higher continence and tolerance rates for the ER formulation.

Solifenacin

Another extended-release option, for the treatment of NDO secondary to SCI, is daily oral solifenacin. Solifenacin is an oral antimuscarinic drug that is thought to selectively bind to the bladder’s M3 muscarinic receptors responsible for contraction of the detrusor. Krebs et al. (2013) conducted a retrospective analysis of case histories and urodynamic data of 35 SCI patients over a 4 year span. Data supporting significantly improved bladder capacity, detrusor compliance, reflex volume and maximum detrusor pressure were reported after an average of 13.1 months of solifenacin treatment.

Oxybutynin

Oxybutynin (OXY) 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 OXY in longer acting forms have sparked renewed research interest with the hopes of reducing side effects observed with the short acting OXY. O’Leary et al. (2003), in a small (n=10) pre-post trial showed that controlled-release OXY 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.

Tolterodine

Although OXY 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 randomized controlled trial (RCT), use of tolterodine was shown to result in significantly increased IC volumes (p<0.0005) and reduced 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 (i.e. failing to detect an effect that is present). As part of the eligibility criteria for this study, subjects were using OXY and IC prior to a 4-day washout in advance of randomization to the tolterodine versus placebo study. This design allowed for a comparison between OXY and tolterodine. The two drugs were found to be equivocal with respect to effectiveness as reflected in 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 TCL, the two medications were only evaluated in a pre-post manner rather than a head to head comparison.

Trospium Chloride

Trospium chloride (TCL; an anticholinergic medication that is reported not to cross the blood-brain barrier) has only recently been approved in North America for use in overactive bladder, where as it has been available in Europe for many years. The efficacy of TCL (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 TCL versus placebo for increased bladder capacity and compliance, and decreased bladder pressure with low side effects. No effect was reported for flow rate and residual urine volumes. Horstmann et al. (2006) found that TCL improved reflex volume, cystometric capacity, and maximum detrusor pressure. Presumably the psychometrically measured cognitive changes seen with medications such as oxybutinin are not seen with TCL as it does not cross the blood brain barrier. However, psychometric testing has not been examined specifically in persons with SCI taking TCL.

In a randomized, double-blind, multicenter trial directly comparing TCL (20 mg bid) versus OXY (5 mg tid) for 2 weeks in the treatment of detrusor hyperreflexia in 95 individuals with SCI, objective urodynamic parameters (maximum bladder capacity and maximum voiding detrusor pressure during micturition) showed that that two medications were equally efficacious (Madersbacher et al. 1995). However, TCL emerged superior with respect to fewer reports of severe dry mouth (4% versus 23%) and subsequently fewer patients treated with TCL withdrew from the study (6% versus 16%).

Comparisons

More recent investigations have been conducted to provide comparison information about the relative efficacy and presence of side effects associated with various anticholinergic drugs (Amend et al. 2008; Stohrer et al. 2007). Stohrer et al. (2007) showed similarities in efficacy in a comparison study of propiverine versus OXY that employed a double-blind, RCT 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 27 subjects whose symptoms of incontinence did not completely resolve with an initial treatment option – 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 / OXY, 2) TCL/tolterodine or 3) OXY/TCL and demonstrated that 85% of patients were treated successfully with a combination treatment option, despite having mostly unsatisfactory outcomes with a single medication. Each initial medication was maintained at the high dose (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 for potential consequences on heart rhythm when administering doses of mixed anti-cholinergics. However, neither study reported conducting an electrocardiogram and therefore concerns about potential cardiac abnormalities incurred by those receiving a combination treatment may need further consideration and investigation.

In addition, Kennelly et al. (2009; n=24) reported that a transdermal method of oxybutinin was effective in increasing the proportion of clean IC 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. Along with these positive effects there were, more importantly, fewer side effects than typically reported with oral delivery, even at up to three times the standard dose.

The acetylcholine blocking property of anticholinergics and their effectiveness on treatment of overactive bladder was indirectly established through the double-blind, placebo controlled study of cisapride, which facilitates acetylcholine delivery to effect smooth muscle motility, and its effect on cystometric parameters in SCI patients (Wyndaele & Van Kerrebroeck, 1995; n=21). No significant difference in pre- and post- (4 weeks at 10mg oral four times daily) urodynamic parameters in both active and placebo groups represents level 6 evidence that puts to rest earlier claims (5 small level 4 and 5 studies from the early 1980s and 1990s) that advocated the use of cisapride in spinal cord injured people with hyperreflexic bladders. Wyndaele and Van Kerrebroeck did report some variable positive effects of cisapride (but not placebo) when cystometric parameters (max capacity and at first contraction, detrusor pressure, compliance, and residual urine) were observed individually, but the clear influence of cisapride was not apparent.  

Conclusion

There is level 1a evidence (from three RCTs; Stohrer et al. 1999; Stohrer et al. 2007; Stohrer et al. 2013) 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.

There is level 1 evidence (from a single RCT; Stohrer et al. 2013) that demonstrated superiority for continence and tolerability when propiverine extended-release is compared to immediate release formulations.

There is level 4 evidence (from a single case series; Krebs et al. 2013) suggested that solifenancin id (10 or 5 mg) is effective in improving bladder capacity, detrusor compliance, reflex volume and maximum detrusor pressure in individuals with neurogenic detrusor overactivity secondary to SCI.

There is level 1 evidence (from a single RCT Ethans et al. 2004) that supports the use of tolterodine versus placebo to significantly increase intermittent catheterization volumes and decrease incontinence in neurogenic detrusor overactivity.

There is level 2 evidence (from a prospective controlled trial; Ethans et al. 2004) that tolterodine and oxybutynin are equally efficacious in SCI patients with neurogenic detrusor overactivity except that tolterodine results in less dry mouth.

There is level 4 evidence (from pre-post studies; O’Leary et al. 2003; Kennelly et al. 2009) that supports the potential benefits of controlled-release oxybutynin as well as a transdermal system for oxybutinin administration, the latter with a reduced side effect profile.

There is level 4 evidence (from a prospective controlled trial; Amend et al. 2008) that suggests benefits such as reduced incontinence and increased bladder capacity from combination treatments of two of oxybutinin, trospium chloride or tolterodine, even in patients with unsatisfactory outcomes following a trial with one of these medications.

There is level 1a evidence (from two RCTs; Stohrer et al. 1991; Madersbacher et al. 1995) that support 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.

There is level 1b evidence (from one RCT; Wyndaele & Van Kerrebroeck 1995) that demonstrates that cisapride is not clearly effective in the treatment of hyperreflexic bladders in individuals with SCI.

  • 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 (particularly the extended-release formula), 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.

    Cisapride is not an effective treatment for hyperreflexic bladders in individuals with SCI.

Toxin Therapy for SCI-Related Detrusor Overactivity

Botulinum Toxin Type A

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 NDO treatment in individuals with SCI and multiple sclerosis. Although anti-cholinergic medications remain first line therapy for this dysfunction, the advantage of botulinum toxin over systemic administration of medications is that botulinum toxin is used focally in the bladder; thus, it avoids systemic side effects, for the most part. There are various types of botulinum toxin available, including various types of BTX-A. When evaluating the literature in this area, one must be aware that although abobotulinumtoxin (AboBTx) and onabotulinumtoxin (OnaBTx) are both derived from BTX-A, they are very different and unit values cannot be compared or interchanged. There are also interesting clinical differences in using botulinum toxin for detrusor overactivity as opposed to spasticity and other neurological conditions; the effect of injecting into the detrusor lasts for 6-12 months, 2-3 times that expected for spasticity. Possible reasons for this is that 1) there is less or no peripheral nerve re-sprouting to reform the neuromuscular junctions in smooth muscle, and 2) the mechanism of blocking afferent C-fibre activity in the membrane bound vesicles of the afferent pathways and the urothelium is an additional effect to the traditionally understood blocking at the neuromuscular junction in the efferent pathway.

Table: Botulinum Toxin Type A

Discussion

In 2013, Mehta et al. published a large systematic review and meta-analysis examining the effect of botulinum toxin A on improving bladder function post SCI. In total, fourteen studies met inclusion criteria including one RCT (Schurch et al. 2005), one case-control (Grosse et al. 2009), and twelve pre-post studies (Schurch et al. 2005, Del Popolo et al. 2008, Game et al. 2007, Giannantoni et al. 2009, Klaphajone et al. 2005, Kuo et al. 2006, Kuo et al. 2008, Pannek et al. 2009, Tow et al. 2007, Wefer et al. 2010; Akbar et al. 2007, Patki et al. 2006). Ten studies examined OnaBTx and four studies examined aboBTx. The meta-analyses revealed large effect sizes and a significant increase in reflex detrusor volume (1, 3, 6 months, p<0.001 for all), bladder capacity (1, 3, 6, 12 months, p<0.001 for all), bladder compliance (1, 3, 6, 12 months, p<0.001 for all), and post-residual urine volume (1, 3, 6 months, p<0.001 for all). There was also a mean decrease in catheterization frequency (p<0.001) and number of incontinence episodes post treatment. Finally, Mehta et al. (2013) reported that there was no significant deterioration in maximum flow rate observed as a result of treatment (p=0.403). Three mild adverse effects were reported: hypertension (Tow et al. 2007), muscular weakness (Akbar et al. 2007), and stress urinary incontinence (Del Popolo et al. 2008). While this systematic review reported optimistic findings, it was unable to assess comparisons in botulinum toxin A type, different dosing schedules, control groups, or location sites.

Four RCTs have been published between 2007 and 2012 on the effectiveness of botulinum toxin for NDO post SCI; these studies were not included in the aforementioned systematic review and meta-analysis by Mehta et al. (2013). In a placebo-controlled RCT, Herschorn et al. (2011) examined the effect of 300U onaBTX injections into the intradetrusor to improve NDO. The authors found that onaBTX reduced incontinence episodes and maximum detrusor pressure during filling compared to controls (p<0.001 for both) at 6, 24, and 36 week follow-up. Similarly, void volume and cystometric capacity increased more for the treatment group compares to controls (p<0.001 for both). The authors reported minimal adverse effects such as muscle weakness and UTI. In a small RCT by Abdel-Meguid et al. (2010), subjects were randomized to receive onaBTX into either the intradetrusor only or both the intradetrusor plus intratrigonal. The authors reported improvements in all urodynamic parameters (incontinence episodes, complete dryness, reflex volume, cystometric capacity and maximum detrusor pressure) among both groups; however, only improvements in incontinence episodes, complete dryness and reflex volume were significantly greater in the combined group compared to the detrusor-only group (p<0.001 for all). Finally, a small RCT by Krhut et al. (2012) compared the effect of onaBTX to the detrusor versus suburothelial on a number of urodynamic parameters amongst a group of individuals with NDO secondary to SCI. The following urodynamic parameters improved for both groups, although there was no significant difference between groups: number of incontinent episodes, frequency of catheterizations, maximum detrusor pressure, void volume, cystometric capacity, and volume at first involuntary detrusor contraction. Krhut et al. (2012) reported favouring the suburothelial injections over the intradetrusor since injections could be better localized. Finally, one RCT demonstrated that onaBTX injected into the intradetrusor in either 200U or 300U produce greater improvements in quality of life (QoL) than individuals receiving the placebo (Schurch et al. 2007).

Two important RCTs (Cruz et al. 2011; Ginsberg et al. 2012) served as the basis for BTX-A being approved in Canada, the US, and Europe; however, the patient population is mixed, including individuals with SCI and multiple sclerosis. While this does not meet SCIRE inclusion criteria, it was felt that it was important to note these two RCTs as they have been pivotal in influencing the use of this treatment in clinical practice. 

Conclusion

There is level 1a evidence (from several RCTs) that 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.

There is level 4 evidence (from one pre-post and one case series study; Klaphajone et al. 2005; Caremel et al. 2011) that detrusor contractility may be decreased through repeated BTX-A injection. 

  • Onabotulinum toxin type A injections into the detrusor muscle improve neurogenic destrusor overactivity and urge incontinence; it may also reduce destrusor contractility.

Capsaicin and Resiniferotoxin

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 topical patches available for allodynia pain in Europe. Capsaicin induced localized and reversible anti-nociception results from 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; however, it has less irritation to the bladder and is therefore better tolerated. By chemically reducing C-fiber bladder afferent influence with intravesical vanilloids (i.e., CAP, RTX), bladder contractility is decreased and bladder capacity is increased (Evans 2005). 

Table: Capsaicin 

Discussion

DeSeze et al. (1998) has provided level 1b evidence in support of the ability of CAP to improve bladder function. The authors found that 30 days after CAP instillation, compared to placebo, it was effective in decreasing 24h voiding frequency (p=0.016), decreasing 24h leakages (p=0.0008), increasing maximal cystometric capacity (p=0.01). This study offers support to other small, non-RCT studies that reported significant CAP-induced increases in bladder capacity (Das et al. 1996; Dasgupta et al. 1998). However, a small RCT cross-over study did not find differences in bladder improvement between individuals receiving CAP versus placebo (Petersen et al. 1999).

George et al. (2007) described the use of a one time instillation of CAP 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 CAP 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 OXY versus propantheline instillation, CAP evaluations could not be blinded and therefore, a discussion of OXY versus propantheline results was undertaken separately.

Dasgupta et al. (1998) confirmed the presence of metaplasia, dysplasia, and flat carcinoma in situ after treatment with Intravesical CAP. All biopsies were determined to be benign but some showed signs of chronic inflammation; this finding has been supported by a small cross-over RCT by Petersen et al. (1999). Dasgupta et al. (1998) reported that 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.

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. The increase in persistent clinical improvements due to RTX over CAP at 90 days follow-up was not statistically significant. Although there was also a statistically significant increase in suprapubic pain with CAP, it was clinically tolerable and brief (p<0.04).

Despite non-significant findings reported in a small non-RCT by Shin et al. (2006), the efficacy of RTX has been confirmed one RCT (Silva et al. 2005) and two pre-post studies (Watanabe et al. 2004; Lazzeri et al. 1998). Compared to placebo, Silva et al. (2005) found that RTX was responsible for significantly increased volume of first involuntary detrusor contraction (p=0.03), maximum cystometric capacity (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 RTX dosing. Despite the small sample size in each dose category, maximum cystometric capacity increased by 53% and 48% for doses of 0.5 uM and 1.0 uM, respectively, by 3 weeks post-treatment. Similarly, incontinence episodes decreased by 51.9% and 52.7%, respectively. 

Conclusion

There is level 1a evidence (from four RCTs and three level 4 studies; Silva et al. 2005; deSeze et al. 2004; Kim et al. 2003; deSeze et al. 1998) that the use of vanillanoid compounds such as capsaicin or resiniferatoxin increases maximum bladder capacity, and decreases urinary frequency, leakages, and pressure in neurogenic detrusor overactivity of spinal origin.

There is level 4 evidence (from one post test study; Dasgupta et al. 1998) that intravesical capsaicin instillation in bladders of individuals with SCI does not increase the rate of common bladder cancers after 5 years of use. 

  • Vanillanoid compounds such as capsaicin or resiniferatoxin increase maximum bladder capacity, and decreases urinary frequency, leakages, and pressure in neurogenic detrusor overactivity.

    Intravesical capsaicin instillation in bladders of individuals with SCI does not increase the rate of common bladder cancers after 5 years of use.

Nociception/Orphanin Phenylalanine Glutamine

Table: Nociception/Orphanin Phenylalanin Glutamine

Discussion

Nociceptin/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 versus 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

There is level 1a evidence (from two RCTs; Lazzeri et al. 2003; Lazzeri et al. 2006) that supports the use of nociceptin/orphanin phenylalanine glutamine, a nociceptin orphan peptide receptor agonist for the treatment of neurogenic bladder in SCI.

  • Nociceptin/orphanin phenylalanine glutamine, a nociceptin orphan peptide receptor agonist, may be considered 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 anticholinergics such as OXY and propantheline which are presented below. Most of these protocols consist of dissolving the medication in a liquid solution, and instilling the medication after emptying the bladder by IC, then leaving it in place until the next scheduled intermittent catherization. 

Table: Intravesical Instillations for SCI-Related Detrusor Overactivity

Discussion

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

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

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

Haferkamp et al. (2000) studied addition of intravesical OXY instillation in patients who performed IC five times daily and who were not adequately treated with oral anticholinergic medication (n=15) and/or experienced intolerable side effects from the oral medication (n=13). Four additional pediatric patients were included who had difficulty swallowing OXY tablets. Of the 32 patients with SCI and neurogenic bladder function, 21 patients became continent with a standard dosage (0.3-0.7mg/kg/day) and 11 patients required a higher dosage (0.9mg/kg/day). Only two patients treated with the higher dose complained of constipation and dryness of the mouth; none of the patients withdrew from treatment.

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

Intravesical instillation of OXY (5 mg suspended in 10 ml water) combined with clean IC was reported to increase bladder capacity in a group of 12 patients (SCI n=8) with neurogenic bladder dysfunction (Prasad & Vaidyanathan 1993). Six to 12 months of follow-up revealed significantly improved maximum cystometric capacity and vesical compliance (both p<0.001), and decreased clean IC frequency (p<0.05), for up to 240 minutes after removal of the drug. Notably, no local or systemic side effects were reported.

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

In contrast, Singh and Thomas (1995) presented a pre-post study with OXY instillations (10 mg) in 6 male patients who had the Brindley anterior root stimulator implanted, and were unable to show any significant improvements in peak detrusor pressure during voiding and peak flow rate. Considering OXY effectiveness in patients managing their bladder with catheterization, the question of the requirement of an intact sacral arc may be relevant to the mechanism of action for OXY.

Conclusion

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

There is level 4 evidence (from a pre-post study; George et al. 2007) that supports the use of capsaicin intravesical instillation to improve leak volume and frequency. However, this study also revealed that capsaicin intravesical instillation worsened residual volume and cystometric capacity, and can induce hyperreflexia in patients with SCI and neuropathic bladder.

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

There is level 4 evidence (from three pre-post studies; Haferkamp et al. 2000; Pannek et al. 2000; Ersoz et al. 2010) that suggest instravesical instillation of oxybutynin is an effective adjuvant therapy for patients with SCI managing their neuropathic bladder with catheterization and oral oxybutynin.

There is level 4 evidence (from one pre-post study; Singh & Thomas 1995) that intravesical oxybutynin instillation is not effective in male, SCI patients with an implanted Brindley anterior root stimulator.

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

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

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

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

Other Pharmaceutical Treatments for SCI-Related Detrusor Overactivity

There are other therapies reported to decrease NDO 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 SCI (e.g., intrathecal baclofen and 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 1990s 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

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. An RCT by Gacci et al. (2007) examined the effect of vardenafil injections compared to placebo injections on maximum detrusor pressure, maximum cystometric capacity, and destrusor overactivity volume among 25 individuals with SCI. The authors reported a significant improvement in the vardenafil group compared to the placebo group (p<0.001 for all).

Chartier-Kastler et al. (2000a) specifically used test bolus intrathecal injections of clonidine (ITC) to investigate its effects on SCI NDO in patients otherwise resistant to a combination of oral treatment and self-IC. 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 specifically for the treatment of genitourinary function in 10 patients with severe spasticity post SCI. Compared to 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. Steers et al. (1992) recommend the use of intrathecal baclofen 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 (e.g., spasticity).

Conclusion

There is level 1b evidence (from one RCT and one pre-post study; Gacci et al. 2007; Taie et al. 2010) that phosphodiesterase-5 inhibitors may be beneficial in improving bladder function post SCI.

There is level 1b evidence (from one RCT; Steers et al. 1992) that intrathecal baclofen may be beneficial for bladder function improvement in individuals with SCI when oral pharmacological interventions are insufficient.

There is level 4 evidence (from one case series; Chartier-Kastler et al. 2000a) that the use of intrathecal clonidine improves detrusor overactivity in individuals with SCI when a combination of oral treatment and sterile intermittent catheterization is insufficient.

  • Tadalafil, vardenafil, 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 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 IC have failed to create an adequate bladder volume under low pressure for storage (Chartier-Kastler et al. 2000b; Quek & Ginsberg 2003). Intolerable incontinence, renal deterioration, and 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. 2000a; 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 section 3.4.6 Continent Catheterizable Stoma and Incontinent Urinary Diversion).

Table: Surgical Augmentation of the Bladder to Enhance Volume

Discussion

Like 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 (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 pre-post (cohort) study designs (Chartier-Kastler et al. 2000b). 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, 8 and 14.7 years by Nomura et al. (2002; n=21), Quek and Ginsberg (2003; n=26), and Gurung et al. (2012; n=19), respectively. Chartier-Kastler et al. (2000b) conducted a prospective evaluation of 17 persons with longstanding traumatic 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 and Kuo (2009) reported on 40 adults with SCI. Gobeaux et al. (2012) presented data on 61 SCI patients who underwent supratrigonal cystectomy with Hautmann pouch.

Augmentation ileocystoplasty, Mitrofanoff appendicovesticostomy, Kock ilial reservoir, and Indiana pouch are described by Zommick et al. (2003) as efficacious lower urinary tract reconstruction options for select tetraplegic patients. 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, significant resolution of incontinence occurred in the majority of patients. Chartier-Kastler et al. (2000b) 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 most 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 IC and use of Crede maneuver) with the vast majority of these responding well to conservative treatment (Chartier-Kastler et al. 2000b; 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; Zommick et al. 2003). Chen and Kuo (2009) noted, however, that issues with UTI, reservoir calculi and new onset upper-tract urolithiasis that commonly follow the ileoplasty still require resolution. In a retrospective chart review Reyblat et al. (2009) reported equivocal postoperative continence using an extraperitoneal (small peritoneotomy and standard ‘clam’ enteroplasty) versus the standard intraperitoneal augmentation. The extraperitoneal approach resulted in shorter operative time, shorter length of stay, and more 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). Although the Gobeaux et al. (2012) study reflected an impressive average 5.84 year follow-up result of 74% complete continence, decreased rates of infection and preserved upper tract function as measured through urodynamics, the presence of 27.5% of patients with subsequent bowel dysfunction (e.g., new onset diarrhea and/or fecal incontinence resulting from the ileal resection) requires that patients need to be counseled carefully before choosing this intervention as a treatment option. Gurung et al. (2012) did report that although bladder stones are a common complication following cystoplasty, the additional encouraging long-term patient-reported satisfaction would serve to counterbalance the increased risk of this treatable complication.

Conclusion

There is level 4 evidence (from three pre-post, three case series, and one case control; Gobeaux et al. 2012; Chen & Kuo 2009; Chartier-Kastler et al. 2000b; Gurung et al. 2012; Quek & Ginsberg 2003; Nomura et al. 2002; Reyblat et al. 2009) that surgical augmentation of the bladder (ileocystoplasty) may result in improved continence in persons with SCI who previously did not respond well to conservative approaches for overactive bladder.

There is level 3 evidence (from one case control; Reyblat et al. 2009) that extraperitoneal versus 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 versus intraperitoneal augmentation enterocystoplasty may result in better postoperative recovery.

Enhancing Bladder Emptying Pharmacologically

Pharmacological management of dysfunctional bladder emptying is based on understanding the neuroanatomy of the lower urinary tract. The normal coordinated effort of the lower urinary tract includes bladder storage and emptying. During the filling process, sympathetic adrenergic receptors (e.g., norepinephrine) are responsible for allowing the bladder to store urine. These efferent nerves originate from T11 to L2 and offer inhibitory input to the bladder. Beta-adrenergic receptors populate the smooth muscle of the bladder and stimulation causes bladder wall relaxation. Conversely, alpha-adrenergic receptors are denser in the lower portion of the bladder including the sphincter and stimulation results in increased bladder outlet resistance. The parasympathetic nerves originating from S2 to S4 supply the cholinergic (e.g., acetycholine) receptors that are responsible for bladder contraction as a result of increased excitatory feedback from filling. In individuals with SCI lesions, these pathways may be interrupted and this causes impairment in storing or 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

Relieving symptoms of neurogenic bladder dysfunction by decreasing outflow resistance is achieved by alpha-1 blocking therapy. Protection against complications of chronic urinary retention is the primary intent of therapeutic use of alpha-adrenergic blocking drugs for neurogenic bladder dysfunction management. In a double blind RCT, Perrigot et al. (1996) examined a single intravenous injection of alfuzosin and established it as a test for effective decreases in maximal urethral pressure and relative dose escalation.

Tamsulosin is an alpha-1 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 one 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); however, 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. In a small RCT, Costa et al. (1993) 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 et al. (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 requiring 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. (1993a) 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 resulted in a reduction of bladder outlet resistance, detrusor-sphincter dyssynergia and 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. In a small (n=10) retrospective chart review Linsenmeyer et al. (2002) explored men with upper tract (i.e. kidneys and ureters) stasis secondary to SCI ≥T6who used reflex voiding to manage their bladder. After 6 months of alpha-1 blocker therapy improvement in upper tract stasis was reported for 80% of the sample, as measured by significant decreases in duration of uninhibited bladder contractions. Firm conclusions about effectiveness and the optimum duration of treatment can only be validated with further RCTs.

Conclusion.

There if level 1b evidence (from one RCT; Costa et al. 1993) that moxisylyte decreases maximum urethral closure pressure by 47.6% at 10 minutes after an optimum dose of 0.75 mg/kg in individuals with SCI.

There is level 4 evidence (from one pre-post study; Abrams et al. 2003) that tamsulosin may improve bladder neck relaxation and subsequent urine flow in SCI individuals.

There is level 4 evidence (from oone pre-post and one case series study; Perkash 1995; Chancellor et al. 1993a) 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 (from one case series study; Al-Ali et al. 1999) 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.

  • 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 NDO. Among individuals with sphincter overactivity post SCI, botulinum toxin may 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 improve emptying and possibly eliminate the need for catheterization.

Table: Bladder Emptying through Botulinum Toxin

Discussion

Detrusor external sphincter dyssynergia and associated high bladder pressures, vesicoureteral reflux, and frequent UTIs are associated with poor long-term outcomes for patients. These patients may develop upper tract deterioration and/or suffer incontinence and poor QoL. 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 (2008; 2013). While this author cautions that QoL can decrease due to increased incontinence experienced by some individuals, careful patient selection and combinatorial approaches 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 QoL post injection, but did not reveal data on incontinence.

Kuo (2013) found that combined detrusor and additional low-dose urethral sphincter BTX-A injections in patients with incomplete SCI and detrusor sphincter dyssynergia, was effective in producing less urinary incontinence and preservation of spontaneous voiding. As well, patients with detrusor sphincter dyssynergia and treated only with detrusor BTX-A injections (i.e., 200 U) improved QoL ratings significantly more so than patients treated with only urethral injections (i.e. 100 U).

The improvement found in post-voiding residual volume demonstrated by Kuo (2008, 2013) and Tsai et al. (2009) was initially desmontrated by DeSeze et al. (2002) who conducted a double blind RCT using lidocaine as a control injection (n=8) compared to botulinum toxin A (BTxA) as the active treatment (n=5). DeSeze et al. (2002) 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 from 159.4 mL to 105.0 mL; all patients who previously presented with autonomic dysreflexia no longer exhibited symptoms.

In the clinical setting, a test dose of BTX-A combined with integrated electromyography is the optimal method for evaluation of dose and efficacy. Chen et al. (2010) demonstrated that a single low dose (100 U) of BTX-A, applied into the external urethral sphincter cystoscopically, could be monitored 4 weeks post-injection for objective measures of efficacy. Severe urethral sphincter spasticity as documented through integrated electromyography would advocate for repeated injections or higher doses. Other studies also show 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 approximately 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 in 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 et al. (2009) described a method of transperineal sphincter injections using fluoroscopic guidance and electromyography that resulted in excellent effects on bladder emptying, with most patients returning to voiding. Patients were able to avoid frequent IC 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. 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. 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 one patient was able to spontaneously void after botulinum A injection. 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-guided transperineal injection of 100 U onaBTx to the external urethral sphincter to treat DESD. As the prostate gland represented a key landmark in the transrectal ultrasound-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, and static urethral pressure. The onaBTx injection did not produce a significant decrease in maximal detrusor pressure. This was the first study to demonstrate the effect of transrectal ultrasound -guided transperineal onaBTx injection into the external urethral sphincter 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-A 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 IC 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 is advantageous as it allows one to avoid 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 reducing 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 therapeutic results. Post-injection urodynamic studies should be conducted to prove that resultant voiding pressures are in the acceptable range. For 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 in which patients are 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 one RCT and several controlled and uncontrolled trials; DeSeze et al. 2002) 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 4-Aminopyridine (Grijalva et al. 2010) and isosorbide dinitrate (Reitz et al. 2004). 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

4-Aminopyridine is a potassium channel blocker, prolonging action potentials and increasing neurotransmitter release at the neuromuscular junction. 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 of 12 participants regained both sensation and control of the bladder sphincter, and 1 of 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.

Isosorbide dinitrate is a drug typically used to prevent angina attacks. However, it has been studied for the use of improving bladder function among 12 males post SCI (Reitz et al. 2004). In this single pre-post study, it was found that isosorbide dinitrate reduced external urethral sphincter pressure along with dyssynergic contraction; however, bladder pressures remained unchanged.

Conclusion

There is level 4 evidence (from one pre-post study; Reitz et al. 2004) that isosorbide dinitrate may be effective in reducing eternal urethral pressure and dyssynergic contraction.

There is level 4 evidence (from one pre-post study; Griljava et al. 2010) that 4-aminopyridine, at sufficient dosage, may be effective in restoring sensation and/ or control of the bladder sphincter.

  • Isosorbide dinitrate may improve control of the bladder post SCI; although, 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 such as reflux, infections and even renal failure. The choice of SCI-related bladder management method depends on the type of bladder dysfunction (e.g., incomplete emptying, incontinence, dyssynergia) and other secondary aspects of the SCI such as the patient’s functional capabilities, health, resources and other concomitant conditions. Urodynamic assessment is likely to be necessary in most patients to fully understand the dysfunction in specific structures in the lower urinary tract. Thereafter, the chosen method of bladder management must result in continence, be acceptable to the individual with neurogenic bladder, and facilitate the greatest independence. During rehabilitation and after spinal shock has subsided, people with SCI are initiated with the most conservative treatment options first (Wyndaele 2008). Patients are then taught how to manage the chosen method, and are advised as to complications and alternatives. The section below reviews several papers that address the outcome of groups of patients treated with the spectrum of conservative bladder management methods. 

Conservative methods for bladder management includes behaviour therapy (triggered reflex voiding, bladder expression through Crede and/or Valsalva maneuver, and toileting assistance; catheters (intermittent or indwelling, condom (males only) or other external applicances); pharmacotherapy; and finally electro stimulation (electrical neuromodulation, electrical stimulation of the pelvic floor or intravesically). If residual bladder function permits, spontaneously “triggered” or expression voiding without the need for an external drainage system may be an option, although there are a variety of complications that can result from high bladder pressures with these approaches (Wyndaele et al. 2001). Suprapubic catheterization (SPC) is occasionally chosen in the subacute period given that disturbance to the urethra can be avoided. However, the complication rate remains high for this invasive technique and thus should be chosen only when conservative methods are unsuccessful and must be accompanied by comprehensive education for daily care.

Urodynamic studies provide information on lower urinary tract health, storage and emptying pressure, reflux status, and are essential to the choice of bladder management method(s) individualized for each patient. Having access to urodynamic data can also assist later decision making if changes to management methods are required. Green (2004), Drake et al. (2005), and Yavuser et al. (2000), address these issues, listing some of the common complications as reason for change of management methods: 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 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 more invasive options involving bladder augmentation surgery or stimulator implantation (covered in later sections).

Table: Comparison Studies of Conservative Bladder Emptying

Discussion

A retrospective analysis of 234 patients with incomplete cervical cord injuries (Gohbara et al. 2013) found that during initial rehabilitation, patients were managed by urethral catheterization, suprapubic cyststomy, self or assisted administration of clean IC, clean IC with occasional spontaneous voiding, or spontaneous voiding alone. The severity of paralysis (e.g., AIS score) and urinary sensation (presence/absence of desire to urinate) were found to be predictive parameters for improvement in voiding function over the course of rehabilitation. The majority of patients’ bladder function improved during rehabilitation and those patients who were admitted with catheterization and discharged with spontaneous voiding, did so on average by 85.2 days (range 16-142). An interesting finding in this Japanese study is the high rate of AIS D (80.2%) patients compared to published rates from other international SCI populations (46-59% in Europe, Hogel et al. 2012; 29-32% in the USA, DeVivo 2007, 28% in Canada, Pickett et al. 2006).

In keeping with offering conservative management options first, El-Masri et al. (2012) found that supervised sequential management methods beginning with a brief period of indwelling urethral catheterization followed in IC and/or reflex voiding over the longer term of regular surveillance (8-21 years) and timely intervention, kept complication rates to 62% (compared to 93% reported by Weld & Dmochoswski 2000). Of the 62% of complications, only 22.6% were related to the upper urinary tract.

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 SPC 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) 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 catheters compared to SPC. Each of these methods, resulted in a greater incidence of bladder stones than IC. Ord et al. (2003) reported hazard ratios relative to IC of 10.5 for SPC 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 SPC and found markedly higher rates for those managed with SPC 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 favour IC or triggered spontaneous voiding, it is not always possible to use these methods. Lack of independence for catheterization can limit the use of IC in women and those with tetraplegia (Yavuzer et al. 2000). While every effort is made to start patients on IC programs, some patients change to other methods over 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. Green et al. (2004) found that 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 IC (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.

In select groups of patients such as those with tetraplegia and who are respirator-dependent, use SPC (compared to IC or indwelling catheterization alone or combined with stoma or tapping) resulted in lower urological complications and better QoL, as long as close urological surveillance occurs at least annually (Bothig et al. 2012; n=56). SPC resulted in fewer instances (p<0.05) of ureteric reflux, bladder/kidney stones, or bleeding for high-tetraplegic patients with long-ter-ventilation. SPC was increasingly used with increasing age, regardless of gender.

Conclusion

There is level 4 evidence (from one case series study; El Masri et al. 2012) that severity of injury and urinary sensation could be predictive parameters of future voiding function.

There is level 4 evidence (from one case series study; Gohbara et al. 2013) that supervised, sequential conservative bladder management options result in favourable urological complication rates.

There is level 4 evidence (from two case series studies; Ord et al. 2003; Weld & Dmochowski 2000) that indwelling urethral catheterization is associated with a higher rate of acute urological complications than intermittent catheterization.

There is level 4 evidence (from one case series study; Weld & Dmochowski 2000) 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 (from two case series studies; Ord et al. 2003; Weld & Dmochowski 2000) that intermittent catheterization, whether performed acutely or chronically, has the lowest complication rate.

There is level 4 evidence (from two case series studies; Yavuser et al. 2000; Green 2004) 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 4 evidence (from one case series; Bothig et al. 2012) supporting significantly fewer urological complications and higher quality of life for high-tetraplegic respirator-dependent patients who use suprapubic catheters (versus intermittent catheterization) for bladder management.

  • Supervised sequential conservative bladder management is may result in favourable urological complication rates.

    Severity of injury and urinary sensation could be predictive parameters for future voiding function.

    Intermittent catheterization, whether performed acutely or chronically, may have 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.

    Bladder management via suprapubic catheterization may be the better option for patients that are high tetraplegics and respirator-dependent.

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 first section (3.4.2.1) outlines those studies focusing on specific aspects of IC including timing of catheterization, effectiveness, long-term follow-up, and QoL. The second section (3.4.2.2) outlines studies examining catheter types.

Specific Aspects of using Intermittent Catheterization

Table: Specific Aspects of Using Intermittent Catheterization

Discussion

Intermittent catheterization 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 IC-related higher rates of complications, there is good consensus among the larger retrospective studies available that IC 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; Woodbury et al. 2008).

Perrouin-Verbe et al. (1995) showed that patients most likely to continue with IC 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 (2009b) showed that in patients who employ self-IC and have optimal bladder function, perceived QoL is higher than those with suboptimal function. Akkoc et al. (2013) compared individuals using various bladder management methods; those with normal spontaneous micturition had the highest QoL whereas those using an attendant to perform IC had the lower QoL. The authors reported, however, that there was no difference in personal relationships, general health perception, and sleep/fatigue among groups. These findings are in contrast to those by Oh et al. (2006) who found significant differences in many variables measured by the SF-36 between individuals with SCI and able-bodied controls. It is essential to consider an individual’s activities of daily living, psychological factors (and other concurrent comorbidities) and potential caregiving needs when IC 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 IC programs are detrusor OnaBTx 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).

Finally, in a small RCT, Polliak et al. (2005) used a portable ultrasound device to measure bladder volumes among a group of individuals post SCI. Compared to those who used time-dependent IC, those using volume-dependent IC had significantly fewer catheterizations which resulted in a significant reduction in cost (p<0.001).

Conclusion

There is level 4 evidence (from many non-randomized controls) 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 1b evidence (from one RCT; Polliack et al. 2005) that using a portable ultrasound device reduces the frequency and cost of intermittent catheterizations. 

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

    Portable ultrasound device can improve the scheduling of intermittent catheterizations.

Comparison of Intermittent Catheterization Catheter Types

Table: Comparison of Intermittent Catheterization Catheter Types

Discussion

The traditional catheter used for IC has long been the poly vinyl catheter (PVC) in varying lengths and gauges individualized for each patient. However, recent advances in catheter material, lubricant, and length have led to the development of several new catheter types. Hydrophilic catheters are made of a water-adherent polymer that, when lubricated with water, creates an extremely slippery surface effective for smooth insertion. Frictionless insertion reduces incidence of UTIs, bleeding, and other urinary complications. Other methods to reduce friction include gel-lubricated or pre-coated non-hydrophilic catheters. In total, there have been ten RCTs, and several small non-RCTs, investigating varying types and properties of catheters used for IC.

Several studies and one systematic review (Bermingham et al. 2013) have aimed to determine whether there is a superior catheter type for IC. In a small RCT, Sarica et al. (2010) found that gel-lubricated non-hydrophilic catheters were superior to hydrophilic and PVC catheters in terms of reduced urethral microtrauma and pyuria, and increased patient satisfaction, despite higher cost. However, there was no significant difference rate of UTIs between groups. Giannantoni et al. (2001) also examined pre-lubricated non-hydrophilic catheters versus conventional PVC catheters and demonstrated a reduction in the incidence of UTIs and the presence of asymptomatic bacteriuria. Of note, there were three subjects initially requiring assistance with a conventional catheter transitioning to independence with a pre-lubricated catheter. However, the order of catheter 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. De Ridder et al. (2005) compared hydrophilic catheters to non-coated PVC catheters and found reduced incidence of UTIs in favour of the hydrophilic catheter. Although this multi-centre investigation employed a RCT design (N=123) results should be cautiously interpreted given a 54% drop-out rate.

An additional investigation examined the effect of osmolality on two different hydrophilic catheters. Waller et al. (1997) demonstrated reduced friction with the high-osmality catheter versus 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.

To reduce risk of infection, a new “no touch” ValPro® catheter has been developed and being trialled for use. Denys et al. (2012) performed a crossover RCT whereby patients trialled the ValPro® catheter and a standard catheter. The authors reported that the majority of patients were confident and secure with catheter (>75%) and would recommend it (>50%). It is important to note that bacteremia analyses were not conducted.

To improve QoL and user satisfaction, discrete compact size catheters continue to be developed. Chartier-Kastler et al. (2011) examined the effectiveness of compact catheters compared to standard catheters in a small crossover RCT. The authors reported that patients were more satisfied with the compact versus standard catheters as the former were more discrete when carrying and disposing; further, the standard catheter had greater resistance on insertion. The findings were echoed in a recent, large crossover RCT by Chartier-Kasler et al. (2013) and a small crossover RCT by Biering-Sorensen et al. (2007) where greater satisfaction was reported with use of the compact versus standard catheters.

While catheter length generally reflects the anatomy of the user, some compact catheters are shorter in length (30 cm) than standard catheters (40 cm). A comparison of the two catheters in terms of residual IC urine volume has demonstrated no significant difference in two crossover RCTs (Domurath et al. 2011; Biering-Sorensen et al. 2007). While a third crossover RCT by Costa et al. (2013) found that subjects reported greater satisfaction with standard catheters versus compact catheters for bladder emptying, only descriptive statistics were reported.

A study by Kovindha et al. (2004), provides data on reusable silicone catheters (average of 3 years of usage). The frequency of UTIs reported for the reusable catheter was comparable to that reported for standard disposable catheters (3-7 days of usage), but inferior to frequencies reported for pre-lubricated 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, pre-lubricated 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 1b evidence (from one RCT; Giannantoni et al. 2001) that, compared to conventional poly vinyl chloride catheters, pre-lubricated non-hydrophilic catheters are associated with fewer UTIs and reduced urethral bleeding.

There is level 2 evidence (from one RCT; De Ridder et al. 2005) that, compared to conventional poly vinyl catheters, hydrophilic catheters may be associated with fewer UTIs, but not necessarily urethral bleeding.

There is level 2 evidence (from one RCT; Sarica et al. 2010) that, compared to hydrophilic or conventional poly vinyl catheters, pre-lubricated non-hydrophilic catheters are associated with reduced pyuria and greater patient satisfaction.

There is level 1b evidence (from two RCTs; Giannantoni et al. 2001; Sarica et al. 2010) that, compared to hydrophilic or conventional poly vinyl catheters, pre-lubricated non-hydrophilic catheters are associated with reduced urethral microtrauma.

There is level 1b evidence (from one crossover RCT; Denys et al. 2012) that compared to standard catheters, no-touch catheters may promote greater confidence and security to individuals performing intermittent catheterization post SCI.

There is level 1a evidence (from three crossover RCTs; Chartier-Kastler et al. 2011, 2013; Biering-Sorensen et al. 2007) that, compared to standard catheters, compact catheters may be more discrete for carrying and disposing and therefore provide greater satisfaction to individuals performing intermittent catheterizations post SCI.

There is level 1b evidence (from two cross-over RCTs; Domurath et al. 2011; Biering-Sorecnsen et al. 2007) that compact catheters (30 cm) and standard catheters (40 cm) provide comparable bladder performance with equitable residual urine volume.

  • Although both pre-lubricated and hydrophilic catheters have been associated with reduced incidence of UTIs as compared to conventional PVC catheters, less urethral microtrauma with their use may only be seen with pre-lubricated catheters.

    Compact catheters are more discrete than standard catheters for carrying and disposal but offer comparable performance in bladder emptying and residual urine volumes.

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). Only one 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 (n=4) and Crede (n=1) maneuvers to initiate spontaneous voiding in a small case series of five males with paraplegia (upper motor neuron bladder=3, lower motor neuron bladder=2). Greenstein et al. (1992) note that “Valsalva is defined as increased abdominal pressure using the diaphragm and/or abdominal musculature. The Crede maneuver is suprapubic manual pressure applied over the bladder” (p. 254). Greenstein et al. (1992) 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 (from one case series study; Greenstein et al. 1992) 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 can 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 SPC 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 intermediate catherizations). For example, Ord et al. (2003) noted a significantly greater chance of having bladder stones with long-term SPC 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 intermittent 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 medical illnesses or surgical complications, or severe incontinence. Suprapubic catheterization is occasionally considered during this early period if urethral damage has occurred as a result of prolonged urethral catheter use. Later, in chronic situations, SPC may also be favored by individuals with SCI who are obese, or 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 SPC 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 SPC 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 SPC 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 SPC contain a relatively short follow-up period (<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 SPC 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 versus urethral catheters (Weld & Dmochowski 2000).

A recent study by Katsumi et al. (2010) has shown that regardless of indwelling catheterization method, there were no significant differences in frequency of UTIs or other comparable bladder complications. While each method was correlated with unique complications, one type of catheterization was not superior over the other (Katsumi et al. 2010).

Conclusion

There is level 4 evidence (from four cases series studies, one observational study, and one pre-post study) that despite an associated significant incidence of urological and renal complications, acute and chronic indwelling catheterization may be a reasonable choice for bladder management for people with poor hand function, lack of caregiver assistance, severe lower limb spasticity, urethral disease, and persistent incontinence with intermittent catheterization.

There is level 4 evidence (from one cohort study; Groah et al. 2002) that those with indwelling catheters are at higher risk for bladder cancer compared to those with non-indwelling catheter management programs.

  • With diligent care and ongoing medical follow-up, indwelling urethral and 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.

    Compared to non-indwelling methods, 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 intermittent catherization (Ord et al. 2003; Hackler 1982). However, complications may still arise, as described by Newman and Price (1985). Of greatest concern is incomplete drainage, which may lead to persistently high bladder pressures, recurrent UTI and the likelihood of renal complications including 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 and 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 overcome persistent incontinence that may occur with other methods of bladder management. However, periodic monitoring for bladder “residuals” and complete emptying may be necessarily, as emphasized by Newman and Price (1985) following a review of 60 SCI patients with external catheters. Elevated residuals should raise suspicion of the possibility of excessive bladder pressure resulting from incomplete emptying from a spastic sphincter or areflexic bladder. 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 IC. 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 7.1 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 (from one Newman & Price 1985) that condom drainage may be associated with urinary tract infection and upper tract deterioration.

There is level 4 evidence (from one case series; Perkash et al. 1992) 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 (Zommick et al. 2003; 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 reportedly good up to 60 months (Zommick et al. 2003 [n=7]; Hakenberg et al, 2001 [n=4]), but has not been reported 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). Peterson et al. (2012) observed that during the period from 1998 to 2005 in the USA, urinary diversion was used more frequently by older patients (>41 years, reliant on Medicare) than bladder augmentation as the treatment choice. But due to missing data (e.g., level of injury, failed previous bladder augmentation, renal function status, etc.), the reasons behind treatment choices are not completely understood.

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 IC 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) in 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 occured most concerning of which were those requiring surgical procedures (i.e., 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 to 44 months, which does not provide sufficient long-term safety and effectiveness data. However, given the importance of the clinical achievements (i.e., independent use of intermittent catheterization and 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 that all patients became continent after initially being incontinent prior to surgery. 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 with genital secretions, chronic urethral leakage, and 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) would be beneficial to address this issue.

Colli and Lloyd (2011) evaluated a series of cases (n=35) involving bladder neck closure (BNC) which was paired with permanent 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%). Additional advantages conferred by this technique include a straightforward operative approach without violation of the peritoneum, no need for enteric reconstruction, and possible reduction of bowel complications. Specific disadvantages were noted such as a reduced likelihood of success in very low bladder capacity patients. 

Conclusion

There is level 4 evidence (from one case series and one pre-post study; Hakenberg et al. 2001; Sylora et al. 1997) 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 (from two case series studies; Chartier-Kastler et al. 2002; Kato et al. 2002) 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 1950s 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, 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, 2013) or 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. A systematic review of dorsal genital nerve stimulation in a variety of patients with detrusor overactivity (Farag et al. 2012) confirms its utility in improving bladder capacity and incontinence. As noted previously (Section 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; 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 bladder compliance was mostly unsatisfactory with preimplantation bladder management methods. 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 among participants, even after long-term use (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). 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) gave a Qualiveen questionnaire for assessing bladder health-related QoL and impact of urinary problems. In the study by Vastenholt et al. (2003), the top three 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 QoL 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 the study by Robinson et al. (1988) sphincterotomies were performed on three patients with persistent reflex incontinence, and/or upper tract deterioration, while three 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; Kutzenberger et al. 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. 2001; Kirkham et al. 2002; Bycroft et al. 2004; Hansen et al. 2005). Additionally, rhizotomy alone (without a stimulator) has shown to result in higher QoL 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. It is important to note that the two 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 (Opisso et al. 2013, Martens 2011; Goldman et al. 2008; Opisso et al. 2008; Spinelli et al. 2005; Previnaire et al. 1996; Kirkham et al. 2001; Wheeler et al. 1994) 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. A small (n=11; Opisso et al. 2013) study of three days of dorsal genital nerve stimulation demonstrated the feasibility of at home, self-administered electrical stimulation to increase bladder capacities and void volumes. Previous work by this group (Opisso et al. 2008) showed that training towards self-administration versus automated stimulation was effective in select patients to achieve suppression of undesired detrusor contractions and ultimately increased bladder capacity. Similar results were achieved with conditional stimulation, using implanted or surface electrodes on the dorsal genital nerve to suppress involuntary detrusor contractions (Martens et al. 2011; Horvath et al. 2009; Dalmose et al. 2003). However, further developmental work on larger groups of patients in more rigorous study designs would be required before these or modified approaches could be incorporated clinically as an approach that permits bladder stimulation in the absence of deafferentation. For example, semi-conditional stimulation, which conserves battery life, was also shown to be significantly effective for detrusor overactivity inhibition to increase bladder volume in patients with SCI (Lee et al. 2011). External stimulators, electrodes, cables and tolerance to electrical stimulation in the presence of preserved sensation are considered by patients to be hindrances to acceptability of this intervention (Opisso et al. 2013).

Lee et al. (2005) reported on a group of seven subjects with SCI where transcutaneous versus percutaneous electrical stimulation of the DPN was compared for effectiveness of bladder storage functionality. Although the percutaneous method was superior to the limitations of surface electrodes (e.g., daily donning/doffing, consistent placement and impedance) used for the transcutaneous method, the materials available for percutaneous electrodes are not yet sufficiently durable for long term use. Furthermore, percutaneous stimulation electrodes require precise positioning and potentially introduce a source of infection risk.

In a subsequent report, Lee et al. (2012) presented data from a small (n=6) group of males with SCI and complicated bladder function, using surface electrical stimulation to modulate bladder function. The stimulation paradigm consisted of initial current delivery to the dorsal penile nerve voluntarily triggered after perception of the first bladder contraction and followed by cyclic on-off stimulation parameters pre-determined during a 2-3 day admission to rehabilitation. Vesicoureteral reflux resolved in four cases and bladder wall deformity improved in 5 of the 6 cases, after treatment. Despite the improvement to bladder capacity and compliance, only short-term clinical efficacy was reported. To be a viable longer-term viable solution, not only would long-term follow-up data be required but also patient reported correlates would be required given the potential technical difficulties of this semiconditional stimulation treatment. Dexterity requirements for those with tetraplegia and interference from urine and sweat are among the possible feasibility and acceptability deterrents for this new treatment option.

The importance of current strength of pudendal nerve stimulation for short-term detrusor hyperreflexia inhibition has been explored in chronic suprasacral SCI (Previnaire et al. 1996; Wheeler et al. 1992; Vodusek et al. 1986). During cystometries, current strength at 2.0-3.5 times the bulbocavernosus reflex threshold was required to achieve functional inhibition. However, the subsequent study by Previnaire et al. (1998) determined that daily (i.e., 20 min/day, 5x/wk for 4 wk) stimulation at strengths equal to or above 99 mA applied to the pudendal nerve did not achieve efficacious inhibition of detrusor hyperreflexia.

Yoo et al. 2009 investigated the utility of an intraurethral stimulating catheter to selectively activate the proximal or distal segments of the urethra in 7 individuals with overactive bladder activity secondary to SCI. Although the study confirmed the existence of the pudendal nerve portion of the micturition reflex, further study of the stimulation parameters is required to be able to overcome detrusor dyssynergia and achieve bladder emptying.

Further developmental work would be required before these or modified approaches could be incorporated clinically to improve bladder function when afferent connectivity is intact. Sanders et al. (2011) reported that patients would choose minimally invasive electrode methods to improve bladder function as compared to more invasive methods such as use of the Brindley device (with or without rhizotomy).

Recently, Possover et al. (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 eight persons previously having an explanted Brindley-Finetech stimulator, six 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 two months follow-up compared to baseline. Continued efficacy was reported by the same group in 2013 (Radziszewski et al. 2013).

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 neuromodulation 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 (n=10) and involve fMRI to confirm plastic changes within the brain of those patients undergoing sacral neuromodulation versus 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 six pre-post studies, one case series, and one observational 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 four pre-post studies and one case series study) 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 one pre-post study and one case series study; Madersbacher et al. 1982; Radziszweski et al. 2009) that direct bladder stimulation may result in reduced incontinence, increased bladder capacity and reduced residual volumes (with two year efficacy data from one study group) but requires further study as to its potential for larger scale 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. These non- or minimally invasive techniques are preferred by patients over more invasive methods such as use of the Brindley device, with or without rhizotomy.

There is level 2 evidence (from a one prospective controlled trial; Sievert et al. 2010) 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 one case series study; Katz et al. 1991) 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 one pre-post study; Wheeler et al. 1986) 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 a lack of manual dexterity and when more conservative options have proven unsuccessful (Chancellor et al. 1999; Juma et al. 1995). With the success of transvaginal tape implantation in patients of non-neurogenic stress incontinence, Pannek et al. (2012) sought to evaluate its use for neurogenic stress incontinence in females with SCI but results were unfavourable.

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 conducted in anticipation of emptying the bladder with condom drainage with reflex voiding. Autonomic dysreflexia, a common complication of high volume storage and/or high pressure voiding or leaking in those with SCI typically above T12, can be diagnosed with blood pressure monitoring during cystometrogram and urodynamic studies and subsequently better managed after successful transurethral sphincterotomy (Perkash 2007). Perkash (2007) noted a significant (p<0.0001) decrease in systolic and diastolic blood pressure after transurethral sphincterotomy as well as improved voiding and post-void residuals. However, although diminished symptoms of autonomic dysreflexia were reported, mean maximum voiding pressures changes were not significant.

Juma et al. (1995) conducted a pre post-test of 63 individuals who had received one or more sphincterotomies with a mean follow-up time of 11 years (range 2-30). 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 of 63 individuals having some upper tract pathology (i.e., 12 renal calculi, 11 renal scarring, 1 atrophic kidney, 1 renal cyst), with nineteen deemed significant. Risk of significant upper tract complications in presence or absence of bacteria was 38% and 13%, respectively. Thirty out of 63 individuals had lower tract complications (i.e., 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. Post-void residual volume 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 17 patients with preoperative autonomic dysreflexia (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.1993b, Abdill et al. 1994, Rivas 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/replacement 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.1993b; 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.1993c; 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. Rivas et al. (1994) reported a clear patient bias in favour of the stent because of its short- and long-term reversibility. The authors also concluded that the stent was equivacol to external sphincterotomy in terms of urodynamic values and superior for reasons of reduced surgery, hospitalization, costs and hemorrhage as an adverse event.

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. 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 no more than four individuals at all follow-up timepoints for both groups. There was little difference in subjective assessment of impact of bladder function on QoL 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 two 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 observed in bladder capacity (p=0.30); significant reductions in post-void residual urine volumes (p<0.05) were observed at all follow-up times. Positive urine cultures (i.e., UTI) were noted in 15 of 17 subjects prior to surgery but only in 5, 8 and 4 patients at 3, 6 and 12 months, respectively. Subjective autonomic dysreflexia improved in all nine individuals who had previously experienced AD.

More recently, Patki et al. (2006) reported a small retrospective case series investigation (n=9) of an 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, two patients reported significant recurrrent incontinence, with one implant being removed and the other being revised; by a mean follow-up of 105.2 months, 5 of 9 implants had 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 a cost-effective treatment option (even with implant revisions). Additionally, a retrospective review by Chartier-Kastler et al. (2011) determined an artificial urinary sphincter 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.

Based on the success of safety and efficacy of tension-free vaginal tape for stress incontinence in feamles with neuropathic bladders (N=12; NSCI=3), Hamid et al. 2003 concluded that tension-free vaginal tape was safe for the treatment of women with neuropathic intrinsic sphincter deficiency. Pannek et al. (2012), with the promise of the work of Hamid et al. (2003) and a long history of success in improving continence for women with non-neurogenic stress incontinence, sought to evaluate the use of transobturator tape for women suffering from stress incontinence of neurogenic origin secondary to SCI. Even by eliminating sources of variability for success such as material type and surgical competence, the results of this case series (n=9) yielded unfavourable results. Low cough or valsalva induced leak point pressure incontinence and high complication rates of the procedure led the authors to conclude that the transobturator tape was not a viable option for the treatment of SCI related neurogenic stress incontinence. Other attributions to the interventional failure in this patient population were thought to be related to the specific type and grade of detrusor deficiency and the prevalence of pelvic deformity development (Hobson & Tooms 1992) such as a posteriorly tilted pelvis that would interfere with the position of the obturator foramen.

Conclusion

There is level 4 evidence (from one case series study; Perkash 2007) that sphincterotomy is effective in reducing episodes of autonomic dysreflexia associated with inadequate voiding.

There is level 4 evidence (from one case series study; Pan et al. 2009) that sphincterotomy, as a staged intervention, can provide long-term satisfactory bladder function.

There is level 2 evidence (from a one RCT and several level 4 studies; Chancellor et al. 1999) 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 two treatments was the reduced initial hospitalization associated with the stent, given the lesser degree of invasiveness.

There is level 4 evidence (from one pre-post study and one case series study; Chancellor et al. 1993c; Seoane-Rodriguez et al. 2007) 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 one pre-post study; Juma et al. 1995) that over the long-term, previous sphincterotomy may contribute to a high incidence of various upper and lower tract urological complications.

There is level 4 evidence (from one case series study; Game et a. 2008) 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 (from one pre-post study; Chancellor et al. 1993b) 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 (from one case series study and one pre-post study; Patki et al. 2006 Bersch et al. 2009) 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 one pre-post study; Ke & Kuo 2010) that transurethral incision of the bladder neck may be useful in bladder neck and voiding dysfunction.

There is level 4 evidence (from one case series study; Pannek et al. 2012) that transobturator tape implantation is not effective in managing neurogenic stress incontinence in females living with SCI.

  • 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.

    Transobturator tape implantation is not effective for SCI-related neurogenic stress incontinence and results in high complication rates.

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. It is important to note that overactive bladder may be caused by other urologic abnormalities (e.g., benign prostatic hyperplasia, or UTI that can coexist with other consequences of neurogenic bladder secondary to SCI. Therefore, urodynamic evaluation is critical to assessing overactive bladder before adjuvant therapy is administered. If needed, DDAVP is a synthetic analogue of antidiuretic hormone 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. The utility of spinal root anastomosis in SCI came from groups rediverting the ipsilaterial C7 root to repair brachial plexus injuries with significant long-term effects of motor and sensory function of the upper extremities as a result of compensatory action of the other nerve roots (Gu et al. 2005). Since the brachial and sacral plexuses are organized similarily, the rediversion of local lower extremity nerve roots has been considered a possible, albeit highly invasive, treatment option.

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, respectively, 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 IC in the night while still maintaining continence was greatly reduced (Zahariou et al. 2007) and three 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 three weeks of SCI, bladder balancing was achieved sooner than those which started after three 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; Lin & Hou. 2013, n=9) 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%, 71%, and 78% of patients undergoing T11, L5, and S1 microanastamosis, respectively (Lin et al. 2009, Xiao et al. 2003, Lin et al. 2008 and Lin & Hou 2013). Full recovery of renal function and an absence of UTI was observed at follow-up (i.e., 6-18 months). Of the 7 of 9 patients in the Lin and Hou (2013) study that recovered full bladder storage and voiding function, the return of bladder sensation (able to sense full bladder and desire to void) also accompanied the lack of nocturnal urinary incontinence by 8-12 months postoperatively. Important considerations of this surgical approach are that it is far more invasive than other approaches (i.e., indwelling catherization); and some patients do not show any improvement postoperatively. 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 one RCT; Cheng et al. 1998) 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.

There is level 4 evidence (from one pre-post study and one case series study; Zahariou et al. 2007; Chancellor et al. 1994) 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 pre-post studies; Lin et al. 2009; Xiao et al. 2003; Lin et al. 2008; Lin & Hou 2013) 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 observed most commonly in cauda equina lesions where the sacral reflex is disrupted. However, people with cauda equina lesions may also present atypically with autonomic detrusor contraction which causes a continuous increase of intravesical pressure during urination (Shin et al. 2002). Detrusor areflexia can also occur below the S2 spinal cord level and involve the conus medularis or peripheral nerves. Clinically, this means that the bladder cannot 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, and upper urinary tract damage), 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 males 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 two other studies described in the sections pertaining to DESD therapy there were mixed samples with a few subjects with detrusor areflexia. 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., Table 20 for Other Miscellaneous Treatments). 

Table 21:Detrusor Areflexia

Urinary Tract Infections

Defining Urinary Tract Infections

Urinary tract infections are a common secondary health condition following SCI and a major cause of morbidity (Charlifue et al. 1999; Vickrey et al. 1999). The most prevalent risk indicator of UTI in SCI patients is an indwelling catheter (Biering-Sorensen et al. 2002) or increased duration of catheterization (Foxman 2003). 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 in 1992, and used in the 2006 Consortium for Spinal Cord Medicine Guidelines for Healthcare Providers, have become generally accepted standards for UTI definition. These stipulate that three criteria must be met before an individual with SCI is diagnosed with an UTI: 1) significant bacteriuria, 2) pyuria (urine containing increased white blood cells), and 3) signs and symptoms, as follows:

  • Leukocytes in the urine generated by the mucosal lining
  • Discomfort or pain over the kidneys or bladder, or during urination
  • Onset of urinary incontinence or leakage around the catheter
  • Fever or chills
  • Anorexia
  • Increased spasticity
  • Autonomic hyperreflexia,
  • Cloudy, dark, and/or malodorous
  • Malaise, lethargy, increased sweating, or sense of unease

Significant bacteriuria varies according to the method of urinary drainage and is defined by the following criteria: a) ≥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 SPC, and d) ≥105 cfu/mL for spontaneous management. Treatment of asymptomatic bacteriuria is not recommended, except in the cases of pregnancy and those undergoing urologic procedures (Nicolle et al. 2005) as it has been shown not to be effective and can actually create antimicrobial resistance. In addition, asymptomatic bacteriuria can be effectively treated with antiseptics and urinary alkalinizers or acidifiers (Salomon et al. 2006).

Detecting and Investigating UTIs

Detecting a UTI via identification of symptoms by a 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). These practices are aligned with the recommendations for data capture through the work of the International SCI UTI Basic Data Set working group. This work has been endorsed by the International Spinal Cord Society (ISCoS) Scientific Committee and the American Spinal Injury Association (ASIA) Board. Specifically, the data elements include “date of data collection, length of time of sign(s)/symptom(s), results of urine dipstick test for nitrite and leukocyte esterase, urine culture results and resistance pattern” (Goetz et al. 2013). On resistance patterns, 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

Perhaps understanding risk factors may be the simplest method of initial recognition and management of UTI. Escalrin de Ruz et al. (2000) prospectively followed 128 SCI patients for 38 months. Logistic regression modeling was performed on demographic characteristics, associated factors, urinary drainage methods, type of bladder dysfunction, urological complications and predisposing factors of each infection episode. The results showed that individuals who were completely dependent (FIM score <74) and who had vesicoureteral reflux were at the highest risk for UTI.

Beyond functional characteristics (e.g., FIM scores and type of bladder dysfunction), Massa et al. (2009) found that UTI signs and symptoms were superior predictive factors compared to a patient’s own subjective impression of their own signs and symptoms. The presence of “cloudy urine” had the highest accuracy (83.1%) and a positive dipstick test for the presence of leukocytes had the highest sensitivity (82.8%, highest true positive results). Although the presence of fever reflected the highest specificity (99.0%), its sensitivity was very low (6.9%) for UTI. The authors concluded from this prospective cohort, that basic objective measures such as cloudy urine and positive dipstick results were better at predicting UTI than the patient’s themselves.

However once an UTI is detected, laboratory investigation using microbiological analysis of urine cultures is important for confirming 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, Klebsiella pneumonia, Escherichia 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.

Given the cost and the time spent before results can be obtained with bacterial culture (e.g. 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 respectively as a potential indicator of UTI. The results of investigations into the sensitivity and specificity of dipstick tests in predicting UTI in patient populations other than SCI have been mixed. Hoffman et al. (2004) conducted an investigation to compare dipstick results for nitrites and leukocyte esterase 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 leukocyte esterase or nitrate dipstick was positive; 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 versus 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 versus full investigation. Although this provides good 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 a setting other than an inpatient hospital unit (i.e., not community-based patients) and whether 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 hours (“fresh”) and 24 hours (“refrigerated”) post-refrigeration. The bacterial counts of “mixed” organisms (p=0.10) and Staphalococcus 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 study 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 SPC 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

There is level 4 evidence (from one case series study; Escalrin de Ruz et al. 2000) that patients with SCI who are completely dependent (FIM<74) or who have vesicourethral reflux are at highest risk for UTI.

There is level 4 evidence (from one case series study; Massa et al. 2009) that the presence of cloudy urine or a positive urine dipstick test are better predictors of UTI compared with the patient’s own subjective impression of their own signs and symptoms.

There is conflicting level 4 evidence (from two pre-post studies; Hoffman et al. 2004; Faarvang et al. 2000) concerning whether dipstick testing for nitrates or leukocyte esterase is recommended to guide treatment decision-making.

There is level 1b evidence (from one RCT; Darouiche et al. 1997) 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 level 1b evidence (from one RCT; Horton et al. 1998) 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 level 2 evidence (from one prospective controlled trial study; Shah et al. 2005) that fewer false positive tests showing bacteriuria occur if indwelling or suprapubic catheters are changed prior to collection for urine culture analysis.

  • 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 exposure of the urinary system to foreign bodies and reduce their potential for continued residence by draining the bladder effectively.

Specially Covered Intermittent Catheters for Preventing UTI

Different coatings have been applied to catheters to minimize various complications associated with catheterization and neurogenic bladder and Table 25 outlines studies investigating the effect of hydrophilic catheters on UTI prevention.

Table: Intermittent Catherization 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 versus the conventional PVC catheter. Perhaps most interesting, three 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 et al. (2003), when hydrophilic versus 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 and Hoffman (2009) with the use of hydrophilic catheters versus 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. Cardenas and Hoffman (2009) also included women which allowed for potential gender differentiation in the effect of hydrophilic catheter use. Although females accounted for 29% of the participants, a sample size of 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 is largest RCT to date on this topic. 

Conclusion

There is level 1b evidence (from one RCT; Giannantoni et al. 2001) that, compared to conventional poly vinyl chloride catheters, pre-lubricated non-hydrophilic catheters are associated with fewer UTIs and reduced urethral bleeding.

There is level 2 evidence (from one RCT; De Ridder et al. 2005) that, compared to conventional poly vinyl catheters, hydrophilic catheters may be associated with fewer UTIs, but not necessarily urethral bleeding.

There is level 2 evidence (from two RCTs; Cardenas & Hoffman 2009; Cardenas et al. 2011) that use of hydrophilic versus 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.

Intermittent Catheterization and Prevention of UTIs

Most SCI-related, UTI prevention research has focused on various techniques for intermittent catheterization and these types of studies are summarized in Table 23.

Table: Intermittent Catheterization and Prevention of UTIs 

Table: Systematic Reviews of Intermittent Catheterization and Prevention of UTIs

Discussion

During inpatient rehabilitation, IC is generally the preferred method of bladder management and several prospective studies have compared sterile techniques with traditional or clean techniques of IC (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 versus 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. However, the nature of the historical comparison provides the possibility of confounding variables also affect this result. Both authors noted the greater expense associated with the sterile approach, making it the less attractive option in the absence of evidence for improved positive outcomes.

A meta-analysis of five RCTs comparing the impact of hydrophilic catheters on UTIs in people with SCI found a reduction in the number of UTIs (reduced by 64%) when the hydrophilic catheters were used (compared to non-coated catheters; Li et al. 2013). The coating on the hydrophlic catheters was also successful in reducing urethral trauma (reduced odds of hamturia by ~43%). Despite the general positive effect of hydrophilic catheters versus uncoated catheters, no significant difference was found in single studies for episodes of bacteriuria (Sutherland et al. 1996), number of UTIs (Vapneck et al. 2003) and frequency of symptomatic UTIs (Cardenas & Hoffman 2009). However, the reduced number of UTIs requiring antibiotics, significantly reduced UTI frequency and episodes of hematuria across multiple studies would generally advocate for the use of hydrophilic catheters.

An interesting RCT finding reported by Lavado et al. (2013) reflected a significant reduction of positive urinary cultures in patients randomized to 16 weeks of moderate aerobic physical conditioning compared to controls who were asked to maintain the daily life activities (Lavado et al. 2013). The main outcome of increased peak oxygen consumption in participants of the intervention group, suggested a correlation with an increased immune response attributed to the known beneficial effects of regular physical exercise.

As with all aspects of rehabilitation, a primary goal of bladder training within an inpatient stay is maximal patient independence and self-care. Wyndaele and De Taeye (1990) conducted a prospective control trial (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 two 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 IC for individuals as they move into the community and live with SCI for a prolonged period of time. A prospective controlled trial was conducted by Yadav et al. (1993) comparing UTI incidence rates between those using a clean IC 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 individuals with SCI in the rehabilitation unit versus in the community.

Regardless of the approach to bladder management, and even if IC 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 IC. 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 IC. 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 to be responsible for a lower incidence of UTI compared to the mean values of 40±11 mL for hyperactive bladder or 19±7 mL for hypoactive bladder observed in this study.

Conclusion

There is level 1a evidence (from one meta-analysis of five RCTs; Li et al. 2013) that the use of hydrophilic catheters versus non-coated catheters is effective in reducing the incidence and occurrence of UTI and hematuria.

There is level 1b evidence (from one RCT: Lavado et al. 2013) that regular, moderate aerobic physical activity significantly increases peak oxygen consumption and also significantly reduces the number of patients with positive urinary cultures.

There is level 2 evidence (from two RCTs; Moore et al. 2006; Peta-Fingerhut et al. 1997) that there is no difference frequency of UTI between sterile and clean approaches to intermittent catheterization during inpatient rehabilitation; however, using a sterile method is significantly more costly.

There is level 4 evidence (from one prospective controlled trial; Wyndaele & De Taeye 1990) 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 level 4 evidence (from one prospective controlled trial; Yadav et al. 1993) 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 level 4 evidence (from one pre-post study; Jensen et al. 1995) 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.

Other Issues Associated with Bladder Management and UTI Prevention

Table 26 summarizes studies that compare IC 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: 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 that the response to an 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 SPC  (p<0.05) at 1 year post admission with UTI-related septicaemia the number one cause of death in these patients. Sugimura et al. (2008) also examined the incidence of complications in patients using SPC, 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 (1990a) 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 third 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 (from one prospective controlled trial, one case control study, and one case series study; Joshi & Darouiche 1996; Nwadiaro et al. 2007; Afsar et al. 2013) 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 (from one case control study; Nwadiaro et al. 2007) 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 level 2 evidence (from one RCT; Darouiche et al. 2006) that use of a Statlock device to secure indwelling and suprapubic catheters may lead to a lower rate of UTI.

There is level 2 evidence (from one prospective controlled trial; Gilmore et al. 1992) 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 (from one case series; Ku et al. 2005) 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 for UTI prevention in persons with SCI, as described 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 varying forms (e.g., liquid, capsule). 

Bacterial Interference for Prevention of UTIs

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 either E. coli 83972 (Hull et al. 2000; Darouiche et al. 2005; Prasad et al. 2009) or E. coli HU2117 (Darouiche et al. 2011; Traunter et al. 2007). 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 had 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 versus 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) versus 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. Using a less robust pre-post study design, Prasad et al. (2009) also reported that preinoculation antibiotics improved inoculation rates and that rates of UTI declined during the period of colonization.

A longer period of colonization was achieved in a pre-post study conducted by Hull et al. (2000) in which 21 individuals with longstanding SCI (>18 months) and 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.

An additional strain, E.coli HU2117, when colonized has demonstrated efficacy in preventing symptomatic UTIs from other uropathogens. Traunter et al. (2007) reported that in a group of adult SCI patients, who had been injured for one year or longer, colonization of E.coli HU2117 lead to decreases in the uropathogen Proteus. Further, a RCT conducted by Darouiche et al. (2011) reported that mean number of UTIs per patient was significantly less for those treated with E.coli HU2117 bacterial interference compared to individuals receiving a placebo inoculation. 

Conclusion

There is level 1b evidence (from one RCT and two pre-post studies; Darouiche et al. 2005; Hull et al. 2000; Prasad et al. 2009) that bacterial interference in the form of E. coli 83972 bladder inoculation may prevent UTIs.

There is level 1b evidence (from one RCT and one pre-post; Darouiche et al. 2011; Trautner et al. 2007) that bacterial interference in the form of E.coli HU2117 bladder inoculation may prevent UTIs.

  • E. coli 83972 bladder inoculation may prevent UTIs.


    E.coli HU2117 bladder inoculation may prevent UTIs.

Antibiotic Prophylaxis of 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; Morton et al. 2002). 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; TMX-SMX) as prophylactic measures.

An RCT comparing low-dose, long-term treatment with ciprofloxacin (100 mg nightly) versus 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 twice daily) 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 non-significant (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 may 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-SMX (40 mg and 200 mg, respectively) formulation once daily was found to significantly reduce frequency and relapse rates of bacteriuria (p=0.0001) and symptomatic UTI (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 versus those continuing suppressive therapy (0.043 versus 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% versus 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-SMX (160 mg and 800 mg, respectively) to reduce rates of symptomatic UTI among inpatients 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 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 TMP-SMX 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 1b evidence (from one RCT; Biering Sorensen et al. 1994) that low-dose, long-term ciprofloxacin may prevent symptomatic UTI.

There is level 1b evidence (from one RCT; Gribble & Puterman 1993) that TMP-SMX as prophylaxis may reduce symptomatic UTI rates although conflicting findings were obtained from two prospective controlled trials (Sandock et al. 1995; Reid et al. 1994b). 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 one pre-post study; Salomon et al. 2006) 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.

Antiseptic and Related Approaches for Preventing UTIs

Table: Antiseptic and Related Approaches for Preventing UTIs >

Discussion

Good hygiene practices are imperitive to 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 (1990a) 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 1990b). 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 only washed with standard soap; however, 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 individuals with indwelling or SPC with existing bacteriuria and pyuria (n=89) the effects of sterile saline, acetic acid and neomycin-polymyxin solution bladder irrigants on the degree of bacteriuria/pyuria, or development of antimicrobial resistance; the authors found no significant difference between groups. 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 (Schlager et al. 2005) or 2 g daily ascorbic acid (Castello et al. 1996) for unspecified duration in SCI neurogenic bladder managed with IC or indwelling catheter have proved ineffective in acidifying urine or altering UTI rates.

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 four times daily) 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.

Botulinum toxin therapy has been discussed extensively in this chapter as it relates to improving urodynamic parameters. It has also been studied for the use of reducing UTIs post SCI in two pre-post studies. Both Jia et al. (2013) and Game et al. (2008) reported that after treatment with 300 U into the detrusor, indivudals had significantly fewer UTIs at follow-up. Further, Jia et al. (2013) reported that the reduction of UTIs was significant only in patients with detrusor overactivity but not in those without norm-active detrusors.

Conclusion

There is level 2 evidence (from one RCT; Sanderson & Weissler 1990a) that daily body washing with chlorohexidine and application of chlorhexidine cream to the penis after every catheterization versus using standard soap reduces bacteriuria and perineal colonization.

There is level 1b evidence (from one RCT; Waites et al. 2006) that bladder irrigation with neomycin/polymyxin or acetic acid is not effective for UTI prevention.

There is level 2 evidence (from one RCT; Castello et al. 1996) that bladder irrigation with ascorbic acid is not effective for UTI prevention.

There is level 4 evidence (from one pre-post study; Schlager et al. 2005) that phosphate supplementation is not effective for UTI prevention.

There is level 2 evidence that bladder irrigation with trisdine (RCT; Pearman et al. 1988), kanamycin-colistin (RCT; Pearman et al. 1988) or a 5% hemiacidrin solution combined with oral methenamine mandelate (2 mg four times daily; RCT; Krebs et al. 1984) may be effective for UTI prevention.

There is level 1b evidence (from one RCT; Lee et al. 2007) that oral methenamine hippurate, either alone or in combination with cranberry, is not effective for UTI prevention.

There is level 4 evidence (from two pre-post studies; Jia et al. 2013; Game et al. 2008) that 300 U botulinum toxin type A may reduce UTIs among individuals with neurodestrusor overactivity post SCI.
 

  • 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.

    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).

    Oral methenamine hippurate, either alone or in combination with cranberry, is not effective for UTI prevention.

    Botulinum toxin type A (300 U) injected into the detrusory may prevent UTIs in individuals with neurodetrusor overactivity.

Cranberrry for Preventing UTIs

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 Cochrane systematic review (Jepson & Craig 2008). However, Hess et al. (2008) 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) employed 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 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 pre-post study (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 versus 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 et al. (2004) 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 the studies by Hess et al. (2008), Linsenmeyer et al. (2004), and Waites et al. (2004) lack intent-to-treat statistical analyses which 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 1a evidence (from four RCTs; Lee et al. 2007; Linsenmeyer et al. 2004; Waites et al. 2004; Hess et al. 2008) 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 and preventing 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.

The four aforementioned articles were assessed collectively in a systematic review by Mays et al. (2014). While the authors reported that there is limited positive evidence for educational programs directed towards reducing UTIs, they also note that “As there is no downside to this simple, inexpensive intervention, the data are still supportive of nurses providing education on urinary care and management with their patients” (p. 9).

Conclusion

There is level 2 evidence (from one RCT; Cardenas et al. 2004) 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.

There is level 2 evidence (from one RCT, and two pre-post study; Hagglund et al. 2005; Barber et al. 1999; Anderson et al. 1983) that there are beneficial effects of education mediated by SCI specialist health professionals on reducing UTI risk in community-dwelling individuals with SCI using various approaches (e.g., 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 which is the most effective approach.

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 SPC 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), TMP-SMX, 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 day versus 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 versus 3 days. Although, this high study advocates for the use of a 14 versus 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. 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 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% versus 48%; p=0.003) and day 7 (90% versus 57%; p=0.015). In addition, both treatments were effective at reducing bacterial biofilms at day 4 and 7 (p<0.001), although the biofilm eradication rate was significantly higher with Ofloxacin versus TMP-SMX or other antibiotic at day 4 (62% versus 24%; p=0.005); and day 7 (67% versus 35%; p=0.014). 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 versus 44% of SCI subjects treated with TMP-SMX.     

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 two 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. It was found that there was an overall low rate of success and no difference between the dose strengths or between tobramycin and amikacin even though high antibiotic concentrations were found in the urine of all subjects; this suggests that alternative antimicrobial agents may 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 1b evidence (from one RCT; Dow et al. 2004) that supports the use of 14 versus 3 days of Ciprofloxcin for improved clinical and microbiological outcomes in the treatment of UTI in persons with SCI.

There is level 1b evidence (from one RCT; Reid et al. 2000) 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.

There is level 1b evidence (from one RCT; Sapico et al. 1980) that there is a low success with aminoglycosides for the treatment of UTI post SCI.

There is level 4 evidence (from one pre-post study; Waites et al. 1991) that norfloxacin may be a reasonable treatment for UTI post SCI but subsequent resistance must be monitored.

There is level 4 evidence (from one case series study; Linsenmeyer et al. 1999) that intermittent neomycin/polymyxin bladder irrigation is effective in altering the resistance of the offending bladder organism(s) to allow for appropriate antibiotic treatment.

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

  • 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

  • There is level 1a evidence (from three RCTs; Stohrer et al. 1999; Stohrer et al. 2007; Stohrer et al. 2013) 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.

    There is level 1 evidence (from a single RCT; Stohrer et al. 2013) that demonstrated superiority for continence and tolerability when propiverine extended-release is compared to immediate release formulations.

    There is level 4 evidence (from a single case series; Krebs et al. 2013) suggested that solifenancin id (10 or 5 mg) is effective in improving bladder capacity, detrusor compliance, reflex volume and maximum detrusor pressure in individuals with neurogenic detrusor overactivity secondary to SCI.

    There is level 1 evidence (from a single RCT Ethans et al. 2004) that supports the use of tolterodine versus placebo to significantly increase intermittent catheterization volumes and decrease incontinence in neurogenic detrusor overactivity.

    There is level 2 evidence (from a prospective controlled trial; Ethans et al. 2004) that tolterodine and oxybutynin are equally efficacious in SCI patients with neurogenic detrusor overactivity except that tolterodine results in less dry mouth.

    There is level 4 evidence (from pre-post studies; O’Leary et al. 2003; Kennelly et al. 2009) that supports the potential benefits of controlled-release oxybutynin as well as a transdermal system for oxybutinin administration, the latter with a reduced side effect profile.

    There is level 4 evidence (from a prospective controlled trial; Amend et al. 2008) that suggests benefits such as reduced incontinence and increased bladder capacity from combination treatments of two of oxybutinin, trospium chloride or tolterodine, even in patients with unsatisfactory outcomes following a trial with one of these medications.

    There is level 1a evidence (from two RCTs; Stohrer et al. 1991; Madersbacher et al. 1995) that support 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.

    There is level 1b evidence (from one RCT; Wyndaele & Van Kerrebroeck 1995) that demonstrates that cisapride is not clearly effective in the treatment of hyperreflexic bladders in individuals with SCI.

    There is level 1a evidence (from several RCTs) that 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.

    There is level 4 evidence (from one pre-post and one case series study; Klaphajone et al. 2005; Caremel et al. 2011) that detrusor contractility may be decreased through repeated BTX-A injection.

    There is level 1a evidence (from four RCTs and three level 4 studies; Silva et al. 2005; deSeze et al. 2004; Kim et al. 2003; deSeze et al. 1998) that the use of vanillanoid compounds such as capsaicin or resiniferatoxin increases maximum bladder capacity, and decreases urinary frequency, leakages, and pressure in neurogenic detrusor overactivity of spinal origin.

    There is level 4 evidence (from one post-test study; Dasgupta et al. 1998) that intravesical capsaicin instillation in bladders of individuals with SCI does not increase the rate of common bladder cancers after 5 years of use.

    There is level 1a evidence (from two RCTs; Lazzeri et al. 2003; Lazzeri et al. 2006) that supports the use of nociceptin/orphanin phenylalanine glutamine, a nociceptin orphan peptide receptor agonist for the treatment of neurogenic bladder in SCI.

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

    There is level 4 evidence (from a pre-post study; George et al. 2007) that supports the use of capsaicin intravesical instillation to improve leak volume and frequency. However, this study also revealed that capsaicin intravesical instillation worsened residual volume and cystometric capacity, and can induce hyperreflexia in patients with SCI and neuropathic bladder.

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

    There is level 4 evidence (from three pre-post studies; Haferkamp et al. 2000; Pannek et al. 2000; Ersoz et al. 2010) that suggest instravesical instillation of oxybutynin is an effective adjuvant therapy for patients with SCI managing their neuropathic bladder with catheterization and oral oxybutynin.

    There is level 4 evidence (from one pre-post study; Singh & Thomas 1995) that intravesical oxybutynin instillation is not effective in male, SCI patients with an implanted Brindley anterior root stimulator.

    There is level 1b evidence (from one RCT and one pre-post study; Gacci et al. 2007; Taie et al. 2010) that phosphodiesterase-5 inhibitors may be beneficial in improving bladder function post SCI.

    There is level 1b evidence (from one RCT; Steers et al. 1992) that intrathecal baclofen may be beneficial for bladder function improvement in individuals with SCI when oral pharmacological interventions are insufficient.

    There is level 4 evidence (from one case series; Chartier-Kastler et al. 2000a) that the use of intrathecal clonidine improves detrusor overactivity in individuals with SCI when a combination of oral treatment and sterile intermittent catheterization is insufficient.

    There is level 4 evidence (from three pre-post, three case series, and one case control; Gobeaux et al. 2012; Chen & Kuo 2009; Chartier-Kastler et al. 2000b; Gurung et al. 2012; Quek & Ginsberg 2003; Nomura et al. 2002; Reyblat et al. 2009) that surgical augmentation of the bladder (ileocystoplasty) may result in improved continence in persons with SCI who previously did not respond well to conservative approaches for overactive bladder.

    There is level 3 evidence (from one case control; Reyblat et al. 2009) that extraperitoneal versus intraperitoneal augmentation enterocystoplasty produces equivocal postoperative continence with easier early postoperative recovery.

    There if level 1b evidence (from one RCT; Costa et al. 1993) that moxisylyte decreases maximum urethral closure pressure by 47.6% at 10 minutes after an optimum dose of 0.75 mg/kg in individuals with SCI.

    There is level 4 evidence (from one pre-post study; Abrams et al. 2003) that tamsulosin may improve bladder neck relaxation and subsequent urine flow in SCI individuals.

    There is level 4 evidence (from oone pre-post and one case series study; Perkash 1995; Chancellor et al. 1993a) 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 (from one case series study; Al-Ali et al. 1999) 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.

    There is level 4 evidence (from one case series study; Linsenmeyer et al. 2002) 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 one RCT and several controlled and uncontrolled trials; DeSeze et al. 2002) 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 one pre-post study; Reitz et al. 2004) that isosorbide dinitrate may be effective in reducing eternal urethral pressure and dyssynergic contraction.

    There is level 4 evidence (from one pre-post study; Griljava et al. 2010) that 4-aminopyridine, at sufficient dosage, may be effective in restoring sensation and/ or control of the bladder sphincter.

    There is level 4 evidence (from one case series study; El Masri et al. 2012) that severity of injury and urinary sensation could be predictive parameters of future voiding function.

    There is level 4 evidence (from one case series study; Gohbara et al. 2013) that supervised, sequential conservative bladder management options result in favourable urological complication rates.

    There is level 4 evidence (from two case series studies; Ord et al. 2003; Weld & Dmochowski 2000) that indwelling urethral catheterization is associated with a higher rate of acute urological complications than intermittent catheterization.

    There is level 4 evidence (from one case series study; Weld & Dmochowski 2000) 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 (from two case series studies; Ord et al. 2003; Weld & Dmochowski 2000) that intermittent catheterization, whether performed acutely or chronically, has the lowest complication rate.

    There is level 4 evidence (from two case series studies; Yavuser et al. 2000; Green 2004) 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 4 evidence (from one case series; Bothig et al. 2012) supporting significantly fewer urological complications and higher quality of life for high-tetraplegic respirator-dependent patients who use suprapubic catheters (versus intermittent catheterization) for bladder management.

    There is level 4 evidence (from many non-randomized controls) 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 1b evidence (from one RCT; Polliack et al. 2005) that using a portable ultrasound device reduces the frequency and cost of intermittent catheterizations.

    There is level 1b evidence (from one RCT; Giannantoni et al. 2001) that, compared to conventional poly vinyl chloride catheters, pre-lubricated non-hydrophilic catheters are associated with fewer UTIs and reduced urethral bleeding.

    There is level 2 evidence (from one RCT; De Ridder et al. 2005) that, compared to conventional poly vinyl catheters, hydrophilic catheters may be associated with fewer UTIs, but not necessarily urethral bleeding.

    There is level 2 evidence (from one RCT; Sarica et al. 2010) that, compared to hydrophilic or conventional poly vinyl catheters, pre-lubricated non-hydrophilic catheters are associated with reduced pyuria and greater patient satisfaction.

    There is level 1b evidence (from two RCTs; Giannantoni et al. 2001; Sarica et al. 2010) that, compared to hydrophilic or conventional poly vinyl catheters, pre-lubricated non-hydrophilic catheters are associated with reduced urethral microtrauma.

    There is level 1b evidence (from one crossover RCT; Denys et al. 2012) that compared to standard catheters, no-touch catheters may promote greater confidence and security to individuals performing intermittent catheterization post SCI.

    There is level 1a evidence (from three crossover RCTs; Chartier-Kastler et al. 2011, 2013; Biering-Sorensen et al. 2007) that, compared to standard catheters, compact catheters may be more discrete for carrying and disposing and therefore provide greater satisfaction to individuals performing intermittent catheterizations post SCI.

    There is level 1b evidence (from two cross-over RCTs; Domurath et al. 2011; Biering-Sorecnsen et al. 2007) that compact catheters (30 cm) and standard catheters (40 cm) provide comparable bladder performance with equitable residual urine volume.

    There is level 4 evidence (from one case series study; Greenstein et al. 1992) 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 can lead to renal complications.

    There is level 4 evidence (from four cases series studies, one observational study, and one pre-post study) that despite an associated significant incidence of urological and renal complications, acute and chronic indwelling catheterization may be a reasonable choice for bladder management for people with poor hand function, lack of caregiver assistance, severe lower limb spasticity, urethral disease, and persistent incontinence with intermittent catheterization.

    There is level 4 evidence (from one cohort study; Groah et al. 2002) that those with indwelling catheters are at higher risk for bladder cancer compared to those with non-indwelling catheter management programs.

    There is level 4 evidence (from one Newman & Price 1985) that condom drainage may be associated with urinary tract infection and upper tract deterioration.

    There is level 4 evidence (from one case series; Perkash et al. 1992) that penile implants may allow easier use of condom catheters, thereby reducing incontinence and improving sexual function.

    There is level 4 evidence (from one case series and one pre-post study; Hakenberg et al. 2001; Sylora et al. 1997) 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 (from two case series studies; Chartier-Kastler et al. 2002; Kato et al. 2002) 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 six pre-post studies, one case series, and one observational 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 four pre-post studies and one case series study) 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 one pre-post study and one case series study; Madersbacher et al. 1982; Radziszweski et al. 2009) that direct bladder stimulation may result in reduced incontinence, increased bladder capacity and reduced residual volumes (with two year efficacy data from one study group) but requires further study as to its potential for larger scale 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. These non- or minimally invasive techniques are preferred by patients over more invasive methods such as use of the Brindley device, with or without rhizotomy.

    There is level 2 evidence (from a one prospective controlled trial; Sievert et al. 2010) 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 one case series study; Katz et al. 1991) 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 one pre-post study; Wheeler et al. 1986) 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 one case series study; Perkash 2007) that sphincterotomy is effective in reducing episodes of autonomic dysreflexia associated with inadequate voiding.

    There is level 4 evidence (from one case series study; Pan et al. 2009) that sphincterotomy, as a staged intervention, can provide long-term satisfactory bladder function.

    There is level 2 evidence (from a one RCT and several level 4 studies; Chancellor et al. 1999) 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 two treatments was the reduced initial hospitalization associated with the stent, given the lesser degree of invasiveness.

    There is level 4 evidence (from one pre-post study and one case series study; Chancellor et al. 1993c; Seoane-Rodriguez et al. 2007) 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 one pre-post study; Juma et al. 1995) that over the long-term, previous sphincterotomy may contribute to a high incidence of various upper and lower tract urological complications.

    There is level 4 evidence (from one case series study; Game et a. 2008) 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 (from one pre-post study; Chancellor et al. 1993b) 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 (from one case series study and one pre-post study; Patki et al. 2006 Bersch et al. 2009) 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 one pre-post study; Ke & Kuo 2010) that transurethral incision of the bladder neck may be useful in bladder neck and voiding dysfunction.

    There is level 4 evidence (from one case series study; Pannek et al. 2012) that transobturator tape implantation is not effective in managing neurogenic stress incontinence in females living with SCI.

    There is level 2 evidence (from one RCT; Cheng et al. 1998) 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.

    There is level 4 evidence (from one pre-post study and one case series study; Zahariou et al. 2007; Chancellor et al. 1994) 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 pre-post studies; Lin et al. 2009; Xiao et al. 2003; Lin et al. 2008; Lin & Hou 2013) 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.

    There is level 4 evidence (from one case series study; Escalrin de Ruz et al. 2000) that patients with SCI who are completely dependent (FIM<74) or who have vesicourethral reflux are at highest risk for UTI.

    There is level 4 evidence (from one case series study; Massa et al. 2009) that the presence of cloudy urine or a positive urine dipstick test are better predictors of UTI compared with the patient’s own subjective impression of their own signs and symptoms.

    There is conflicting level 4 evidence (from two pre-post studies; Hoffman et al. 2004; Faarvang et al. 2000) concerning whether dipstick testing for nitrates or leukocyte esterase is recommended to guide treatment decision-making.

    There is level 1b evidence (from one RCT; Darouiche et al. 1997) 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 level 1b evidence (from one RCT; Horton et al. 1998) 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 level 2 evidence (from one prospective controlled trial study; Shah et al. 2005) that fewer false positive tests showing bacteriuria occur if indwelling or suprapubic catheters are changed prior to collection for urine culture analysis.

    There is level 1a evidence (from one meta-analysis of five RCTs; Li et al. 2013) that the use of hydrophilic catheters versus non-coated catheters is effective in reducing the incidence and occurrence of UTI and hematuria.

    There is level 1b evidence (from one RCT: Lavado et al. 2013) that regular, moderate aerobic physical activity significantly increases peak oxygen consumption and also significantly reduces the number of patients with positive urinary cultures.

    There is level 2 evidence (from two RCTs; Moore et al. 2006; Peta-Fingerhut et al. 1997) that there is no difference frequency of UTI between sterile and clean approaches to intermittent catheterization during inpatient rehabilitation; however, using a sterile method is significantly more costly.

    There is level 4 evidence (from one prospective controlled trial; Wyndaele & De Taeye 1990) 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 level 4 evidence (from one prospective controlled trial; Yadav et al. 1993) 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 level 4 evidence (from one pre-post study; Jensen et al. 1995) that differences in residual urine volume ranging from 0-153 ml were not associated with differences in UTI during inpatient rehabilitation.

    There is level 1b evidence (from one RCT; Giannantoni et al. 2001) that, compared to conventional poly vinyl chloride catheters, pre-lubricated non-hydrophilic catheters are associated with fewer UTIs and reduced urethral bleeding.

    There is level 2 evidence (from one RCT; De Ridder et al. 2005) that, compared to conventional poly vinyl catheters, hydrophilic catheters may be associated with fewer UTIs, but not necessarily urethral bleeding.

    There is level 2 evidence (from two RCTs; Cardenas & Hoffman 2009; Cardenas et al. 2011) that use of hydrophilic versus 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 (from one prospective controlled trial, one case control study, and one case series study; Joshi & Darouiche 1996; Nwadiaro et al. 2007; Afsar et al. 2013) 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 (from one case control study; Nwadiaro et al. 2007) 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 level 2 evidence (from one RCT; Darouiche et al. 2006) that use of a Statlock device to secure indwelling and suprapubic catheters may lead to a lower rate of UTI.

    There is level 2 evidence (from one prospective controlled trial; Gilmore et al. 1992) 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 (from one case series; Ku et al. 2005) 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 1b evidence (from one RCT and two pre-post studies; Darouiche et al. 2005; Hull et al. 2000; Prasad et al. 2009) that bacterial interference in the form of E. coli 83972 bladder inoculation may prevent UTIs.

    There is level 1b evidence (from one RCT and one pre-post; Darouiche et al. 2011; Trautner et al. 2007) that bacterial interference in the form of E.coli HU2117 bladder inoculation may prevent UTIs.

    There is level 1b evidence (from one RCT; Biering Sorensen et al. 1994) that low-dose, long-term ciprofloxacin may prevent symptomatic UTI.

    There is level 1b evidence (from one RCT; Gribble & Puterman 1993) that TMP-SMX as prophylaxis may reduce symptomatic UTI rates although conflicting findings were obtained from two prospective controlled trials (Sandock et al. 1995; Reid et al. 1994b). 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 one pre-post study; Salomon et al. 2006) 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 2 evidence (from one RCT; Sanderson & Weissler 1990a) that daily body washing with chlorohexidine and application of chlorhexidine cream to the penis after every catheterization versus using standard soap reduces bacteriuria and perineal colonization.

    There is level 1b evidence (from one RCT; Waites et al. 2006) that bladder irrigation with neomycin/polymyxin or acetic acid is not effective for UTI prevention.

    There is level 2 evidence (from one RCT; Castello et al. 1996) that bladder irrigation with ascorbic acid is not effective for UTI prevention.

    There is level 4 evidence (from one pre-post study; Schlager et al. 2005) that phosphate supplementation is not effective for UTI prevention.

    There is level 2 evidence that bladder irrigation with trisdine (RCT; Pearman et al. 1988), kanamycin-colistin (RCT; Pearman et al. 1988) or a 5% hemiacidrin solution combined with oral methenamine mandelate (2 mg four times daily; RCT; Krebs et al. 1984) may be effective for UTI prevention.

    There is level 1b evidence (from one RCT; Lee et al. 2007) that oral methenamine hippurate, either alone or in combination with cranberry, is not effective for UTI prevention.

    There is level 4 evidence (from two pre-post studies; Jia et al. 2013; Game et al. 2008) that 300 U botulinum toxin type A may reduce UTIs among individuals with neurodestrusor overactivity post SCI.

    There is conflicting level 1a evidence (from four RCTs; Lee et al. 2007; Linsenmeyer et al. 2004; Waites et al. 2004; Hess et al. 2008) to support the effectiveness of cranberry in preventing UTI in patients with neurogenic bladder due to SCI.

    There is level 2 evidence (from one RCT; Cardenas et al. 2004) 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.

    There is level 2 evidence (from one RCT, and two pre-post study; Hagglund et al. 2005; Barber et al. 1999; Anderson et al. 1983) that there are beneficial effects of education mediated by SCI specialist health professionals on reducing UTI risk in community-dwelling individuals with SCI using various approaches (e.g., 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 1b evidence (from one RCT; Dow et al. 2004) that supports the use of 14 versus 3 days of Ciprofloxcin for improved clinical and microbiological outcomes in the treatment of UTI in persons with SCI.

    There is level 1b evidence (from one RCT; Reid et al. 2000) 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.

    There is level 1b evidence (from one RCT; Sapico et al. 1980) that there is a low success with aminoglycosides for the treatment of UTI post SCI.

    There is level 4 evidence (from one pre-post study; Waites et al. 1991) that norfloxacin may be a reasonable treatment for UTI post SCI but subsequent resistance must be monitored.

    There is level 4 evidence (from one case series study; Linsenmeyer et al. 1999) that intermittent neomycin/polymyxin bladder irrigation is effective in altering the resistance of the offending bladder organism(s) to allow for appropriate antibiotic treatment.

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

Key Points

  • Key Points

    Detrusor External Sphincter Dyssynergia Therapy: 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 two 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 (particularly the extended-release formula), 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.

    ·         Cisapride is not an effective treatment for hyperreflexic bladders in individuals with SCI.

     

    Toxin Therapy for SCI-Related Destrusor Overactivity

    ·         Onabotulinum toxin type A injections into the detrusor muscle improve neurogenic destrusor overactivity and urge incontinence; it may also reduce destrusor contractility.

    ·         Vanillanoid compounds such as capsaicin or resiniferatoxin increase maximum bladder capacity, and decreases urinary frequency, leakages, and pressure in neurogenic detrusor overactivity.

    ·         Intravesical capsaicin instillation in bladders of individuals with SCI does not increase the rate of common bladder cancers after 5 years of use.

    ·         Nociceptin/orphanin phenylalanine glutamine, a nociceptin orphan peptide receptor agonist, may be considered for the treatment of neurogenic bladder in SCI.

     

    Intravesical Instillations for SCI-Related Detrusor Overactivity

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

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

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

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

     

    Other Pharmaceutical Treatment for SCI-Related Detrusor Overactivity

    ·         Tadalafil, vardenafil, intrathecal baclofen, and clonidine may be beneficial for bladder function improvement but further confirmatory evidence is needed.

  • Detrusor External Sphincter Dyssynergia Therapy: Enhancing Bladder Volumes Non-Pharmacologically

     

    Surgical Augmentation of the Bladder 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 versus intraperitoneal augmentation enterocystoplasty may result in better postoperative recovery.

     

    Detrusor External Sphincter Dyssynergia Therapy: 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.

    ·         Six 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

    ·         Isosorbide dinitrate may improve control of the bladder post SCI; although, 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.

    ·          

    Detrusor External Sphincter Dyssynergia Therapy: Enhancing Bladder Emptying Non-Pharmacologically

     

    Comparing Methods of Conservative Bladder Emptying

    ·         Supervised sequential conservative bladder management is may result in favourable urological complication rates.

    ·         Severity of injury and urinary sensation could be predictive parameters for future voiding function.

    ·         Intermittent catheterization, whether performed acutely or chronically, may have 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.

    ·         Bladder management via suprapubic catheterization may be the better option for patients that are high tetraplegics and respirator-dependent.

     

    Intermittent Catheterization

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

    ·         Portable ultrasound device can improve the scheduling of intermittent catheterizations.

    ·         Although both pre-lubricated and hydrophilic catheters have been associated with reduced incidence of UTIs as compared to conventional PVC catheters, less urethral microtrauma with their use may only be seen with pre-lubricated catheters.

    ·         Compact catheters are more discrete than standard catheters for carrying and disposal but offer comparable performance in bladder emptying and residual urine volumes.

     

    Triggering-Type or 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 (Urethral or Suprapubic)

    ·         With diligent care and ongoing medical follow-up, indwelling urethral and 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.

    ·         Compared to non-indwelling methods, 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 follow-up) 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.

    ·         Epidural dorsal spinal cord stimulation (T1 or T11) and functional electrical stimulation of the lower limbs are not effective in enhancing bladder function.

     

    Sphincterotomy, Artificial Sphincters, 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.

    ·         Transobturator tape implantation is not effective for SCI-related neurogenic stress incontinence and results in high complication rates.

     

    Detrusor External Sphincter Dyssynergia Therapy: 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 Urinary Tract Infections

     

    ·         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 and 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.

     

    Specially Covered Intermittent Catheters for Preventing UTI

    ·         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 Interference for Prevention of UTIs

    ·         E. coli 83972 bladder inoculation may prevent UTIs.

    ·         E.coli HU2117 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

     

    ·         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.

  •  

 

·       

  •  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).
     
    ·         Oral methenamine hippurate, either alone or in combination with cranberry, is not effective for UTI prevention.
     
    ·         Botulinum toxin type A (300 U) injected into the detrusory may prevent UTIs in individuals with neurodetrusor overactivity.
     
     
     
    Cranberry for Preventing UTIs
     
    ·         It is uncertain if cranberry is effective in preventing UTIs in persons with SCI.
     
     
     
    Urinary Tract Infections: Educational Interventions 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 which is the most effective approach.
     
     
     
    Urinary Tract Infections: Pharmacological Treatment of UTIs
     
     
     
    ·         Ciprofloxin administered over 14 days (versus 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.
     
     
     
     
     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).
     
    ·         Oral methenamine hippurate, either alone or in combination with cranberry, is not effective for UTI prevention.
     
    ·         Botulinum toxin type A (300 U) injected into the detrusory may prevent UTIs in individuals with neurodetrusor overactivity.
     
     
     
    Cranberry for Preventing UTIs
     
    ·         It is uncertain if cranberry is effective in preventing UTIs in persons with SCI.
     
     
     
    Urinary Tract Infections: Educational Interventions 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 which is the most effective approach.
     
     
     
    Urinary Tract Infections: Pharmacological Treatment of UTIs
     
     
     
    ·         Ciprofloxin administered over 14 days (versus 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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    Abdill CK, Rivas DR, Chancellor MB. Transurethral placement of external sphincter wire mesh stent for neurogenic bladder. SCI Nurs 1994;11(2):38-41.

    Abdul-Rahman A, Ismail S, Hamid R, Shah J. A 20-year follow-up of the mesh wallstent in the treatment of detrusor external sphincter dyssynergia in patients with spinal cord injury. BJU International 2010; 106: 1510-1513.

    Abrams P, Amarenco G, Bakke A, Buczynski A, Castro-Diaz D, Harrison S et al. Tamsulosin: efficacy and safety in patients with neurogenic lower urinary tract dysfunction due to suprasacral spinal cord injury. J Urol 2003;170(4 Pt 1):1242-1251.

    Adler US, Kirshblum SC. A new assistive device for intermittent self-catheterization in men with tetraplegia. J Spinal Cord Med 2003;26:155-8.

    Akbar M, Abel R, Seyler TM, Bedke J, Haferkamp A, Gerner HJ et al. Repeated botulinum-A toxin injections in the treatment of myelodysplastic children and patients with spinal cord injuries with neurogenic bladder dysfunction. BJU Int 2007;100(3):639-645.

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