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The Effectiveness of Early Sacral Nerve Stimulation in Improving Bladder-Related Complications and Quality of Life after Acute Traumatic Spinal Cord Injury


Summary | Purposes of the Study | Inclusion Criteria | Exclusions


Summary:

Urinary bladder dysfunction and incontinence have a significant clinical, physical, and quality of life (QoL) burden in patients with spinal cord injury (SCI). Contemporary studies reports bladder problems are the second leading reason SCI patients seek medical care. Nearly 250,000 Americans live with SCI and approximately 74-80% of SCI patients report some degree of bladder dysfunction within 1 year of injury1-4. In addition, spinal trauma was present in 11% of all injuries sustained by military personal deployed to Iraq and Afghanistan; 9% of those injuries resulted in significant spinal cord injury5. The average age of those injured with spinal trauma was 27 years, meaning that there is a high current prevalence and future burden of wounded American Veterans with bladder dysfunction due to spinal cord injury. Loss of descending input from the spinal cord results in predictable changes in the neurological control of bladder function6. Normal bladder control is a balance of the sympathetic and parasympathetic nervous systems. The sympathetic system is tonically active the majority of time and allows storage of urine and maintains continence. Conversely, when the parasympathetic nervous system is activated, bladder contraction occurs allowing for bladder emptying7. There are two types of afferent nerve fibers (those that carry nerve impulses from the bladder to the central nervous system), A-delta fibers and C-fibers. Under normal physiological conditions, bladder distention activates A-delta fibers, which triggers a spinobulbospinal micturition reflex and allows voiding. The other type of afferent fibers (C-fibers) are silent during normal voiding 8. Injury to the spinal cord above the sacral segments interrupts the connection between the brain and spinal autonomic centers and interrupts any ability to volitionally void.

Immediately after SCI, the bladder becomes flaccid or atonic. Over the next several weeks following injury, neuroplasticity alters bladder afferents causing a proliferation of C-fiber afferent fibers within the lining of the bladder or the urothelium. As a result, a new C-fiber-mediated voiding reflex emerges and becomes sensitive to bladder distention, while the A-delta fiber afferent input becomes ineffective at allowing the bladder to store urine. The end result of these changes is a bladder that spasms leading to urinary leakage at even low volumes and has poor compliance such that it will not store a normal amount of urine. Depending on the location of the spinal injury, detrusor-sphincterdyssynergia (DSD) may also occur. When DSD occurs, the bladder and the urinary sphincter contract simultaneously during a bladder spasm resulting in high bladder pressures due to increased outlet resistance. Collectively these changes in the neurological control of the bladder comprise the development of the clinical neurogenic bladder (NGB). Patients with NGB carry a heavy burden of disease and over 42% of SCI patients are hospitalized for urinary problems every year 4. The goals of NGB management are well established in the literature: (1) prevention of kidney damage or failure by keeping bladder pressures low (2) preservation of urinary continence and (3) optimizing quality of life. Clinicians use anticholinergic medications or onabotulinum toxin A to relax or paralyze the bladder musculature and minimize bladder spasticity. By decreasing bladder spasticity, a low-pressure system is established, which protects renal function and allows patients to store urine without significant incontinence. Patients must also employ some form of assisted bladder emptying, such as an indwelling catheter or clean intermittent catheterization (CIC) to drain the bladder. These strategies can significantly reduce urinary complications and related hospitalizations, especially in those
patients who tolerate the medications and have the dexterity to perform CIC independently. However, there is a significant inconvenience, potential dependence on others, and often continued leakage that leads to patient noncompliance and discontinuation of CIC4,9,10. Patients who fail these less invasive treatments may require surgical bladder augmentation or urinary diversion in order to preserve renal function11. Bladder augmentation and urinary diversion surgery are both effective, but are associated with significant surgical morbidity and a 1-3% risk of death from complications. Furthermore patients often require additional surgical care during their lifetime to maintain their complex reconstructed urinary system12.

Complications associated with NGB dysfunction and management. In the past, renal failure and urinary sepsis were the major causes of death in SCI patients after recovery from initial injury13. However, advances in urologic care, specifically the introduction of CIC in the 1970’s revolutionized the care of SCI patients14,15. In contemporary studies, the leading causes of death in SCI patients are now pneumonia and influenza rather than renal failure16-18. As a result of longer life expectancy, the chronic complications of NGB management are more prevalent and cause significant morbidity19. Five primary risks of NGB dysfunction and associated management are described below, namely: urinary tract infection, urinary calculi, bladder cancer, renal dysfunction and pressure ulcers.


Urinary tract infection (UTI): Between 20-56% of persons with SCI experience a UTI annually20,21. UTIs are associated with a high rate of hospitalization. The urinary tract of most SCI patients is chronically colonized despite meticulous technique with CIC. Persons with SCI are at high risk for symptomatic UTIs and sepsis because of the structural and functional urinary tract abnormalities (e.g., elevated urine storage pressures, vesicoureteral reflux) that often accompany SCI.

Urinary calculi: Renal calculi are common in patients with SCI with a 7-20% risk of developing a stone over a period of 8-10 years22-24, significantly higher than in the general population25. SCI-associated stones are frequently large, can require multiple procedures to treat and have a high incidence of recurrence26. Renal calculi are associated with an increased odds of death (OR 1.3, 95%CI 1.0-1.7) 18. Bladder calculi are also frequent in SCI, with reported prevalence rates of 18-65%  27 and pathogenesis attributed to foreign bodies (either chronic indwelling or CIC), urinary stasis and infection28. Management of urinary calculi in patients with SCI carries a higher risk of urosepsis and respiratory failure than the same procedures in the general population. This morbidity is directly associated with the level of SCI injury29.

Bladder cancer: The risk of bladder cancer is elevated in SCI patients, especially when managed with an indwelling catheter30. The relative risk of bladder cancer is 4.9 (95% CI 1.3-13.8) in those SCI patients managed with an indwelling catheter as compared to those without indwelling catheters31. In SCI, bladder cancer also typically presents at a younger age and more advanced stage, so survival is poor compared with the general population30,32,33.

Renal dysfunction: Historically, renal failure was a frequent cause of mortality in SCI, but has significantly improved bladder pressure management. In addition to chronic health conditions, renal failure in SCI results from recurrent UTIs and pyelonephritis, urinary calculi, hydronephrosis and NGB dysfunction. Current prevalence of chronic kidney disease (eGFR <60ml/min/1.73 m2) in the US
veterans administration SCI population is 10.2%.


Pressure ulcers (PrU): The relationship between NGB dysfunction, bladder management method and PrU is less direct. Bladder and bowel incontinence have been suggested as risk factors for PrU in some studies but not in others34- 36. A proposed mechanism of PrU resulting from incontinence is wetness of the skin resulting in softening of the protective nature of the dermis and accelerating the impact of pressure on the skin, an effect which is more pronounced when the wetness is due to urine37. PrU prevalence is 39% over three years in Veterans with SCI38, and grade 3-4 PrU are well established risk factors for mortality in SCI18.

Previous study of NGB treatment has focused on how to best control pressures in the bladder, as well as minimize complications once chronic NGB dysfunction has developed after the acute phase of SCI has past. Very few studies have attempted to prevent or ameliorate the adverse sequelae of NGB dysfunction in the acute phase of SCI. Since chronic NGB cannot be reversed, prevention of
the development of some of the worst aspects of NGB such as high pressures and spasticity may be the next best strategy.

Sacral neuromodulation (SNM) is an available technology, which may mitigate the effects of SCI on the bladder. Over the past 20 years SNM has become an established treatment for refractory urinary urge incontinence, urinary frequency/urgency syndrome, non-obstructive idiopathic urinary retention and chronic fecal incontinence39-42. Since first FDA approval in 1997 for refractory urinary urge incontinence, more than 40,000 people have been implanted with SNM devices43. The surgical procedure is minimally invasive and has very few risks. A quadripolar electrode is placed with fluoroscopic guidance adjacent to the S3 nerve routes within the sacral foramen. An internal pulse generator (IPG), much like a cardiac pacemaker, is connected to the electrode and the S3 nerve is stimulated with varying patterns and intensity. The mechanism of action of neuromodulation in humans is not well understood, but it is thought to be through the same afferent sensory nerve fibers (A-delta and C), which are implicated in the development of NGB.

Sacral neuromodulation has a very well established track record in the treatment of patients with non-neurogenic urinary and fecal dysfunction. In the US, the InterStim Therapy System (Medtronic, Minneapolis, MN, USA) has been FDA approved for use in idiopathic overactive bladder (OAB) since 1997, urinary frequency/urgency syndrome and non-obstructive idiopathic urinary retention since 1999, and for chronic fecal incontinence since 201144. Efficacy is well established for all three uses. In idiopathic OAB, SNM achieves sustained therapeutic success in 85% of patients with a greater than 60% reduction in leaks per day. From a quality of life standpoint, 80% of subjects report significant improvement in their urinary symptoms45. Similar improvements with SNM are noted when treating chronic fecal incontinence, with 86% of patients achieving therapeutic success. In this study, patients had decrease in fecal incontinence episodes from a mean of 9.4 at baseline to 1.7, which was durable after 3 years of follow up46.

While the effectiveness of SNM has been well established in non-neurogenic disorders variable success has been achieved in the treatment of chronic NBG47- 52. In regards to the treatment of neurogenic overactivity specifically, results from several studies demonstrate improvement40,53. In one study of 39 patients with mixed NGB etiologies, 80% of patients were able to achieve complete continence and 43% no longer required anticholinergic medications40. Both bladder capacity and bladder compliance have also been shown to improve with SNM. Chartier- Kastler et al were able to demonstrate a mean increase in bladder capacity of ~206 ml in a population of partial SCI patients who had motor function below their injury. SNM in patients with NGB from multiple sclerosis (MS) has been the most studied indication and group in the literature. SNM has been found to reduce frequency of voids per day, reduce incontinence by 4-10 episodes per day, and increase voided volume by 77-84mL per void in this popultation54,55. Multiple studies in MS patients also cite significant improvements in quality of life and patient satisfaction of 75-86%54-56. Importantly, treatment failure in patients with progressive neurologic diseases (such as MS) is thought to be due to disease progression rather than device failure, something that is not present in SCI. The current data in the NGB patient population needs to be interpreted with caution however, due to heterogeneous patient populations, small sample sizes, and lack of randomization. Prospective controlled trials are needed. A randomized clinical trial with a goal enrollment of 54 subjects is currently ongoing to further establish the ideal chronic NGB patient population for SNM57. An important aspect of the treatment of patients with chronic NGB with SNM is that largely the patient groups have good motor function, which is thought to be a fair proxy for a largely intact spinal cord. For instance, ability to ambulate with good motor function below injury or disease has been an important predictor in some studies for success of the procedure.

Despite the success of the above studies in selected populations of patients with chronic NGB, once changes in the neurological control of the bladder have occurred following SCI they are mostly irreversible. In chronic NGB, treatments must be directed at the local muscle level in order to control the high bladder pressures, incontinence and other symptoms. Consequently, the majority of research into the effects of spinal cord injury on the urinary bladder has focused on patients with well-established chronic neurogenic bladder physiology. Interventions during the acute phase of SCI aimed at preventing the developmentof, or reducing the symptoms of NGB, remain an understudied area of research.

Purposes of the Study:

AIM 1: To determine the effect of sacral neuromodulation on urodynamic parameters following acute spinal cord injury. The following outcomes will be evaluated by urodynamic assessment at one year post-SCI: (1) maximum cystometric capacity, (2) bladder compliance, (3) presence of detrusor overactivity, and (4) volume and pressure for first detrusor contraction.

AIM 2: To assess the impact of sacral neuromodulation on patient-reported quality of life after acute spinal cord injury. Patient-reported QoL will be assessed using the SCI-QOL bladder question bank and bladder/voiding diaries (Appendix B). Mean SCI-QOL score, daily number of catheterizations, average catheterization volume, and episodes of incontinence per day will be compared between groups at one year post-SCI.

AIM 3: To examine the impact of sacral neuromodulation on quantifiable clinical outcomes. Patients will be followed longitudinally during the study period and assessed for the following: (1) need for anti-cholinergic medications and/or onabotulinum toxin A treatment, (2) number of symptomatic UTIs per year, (3) complications attributable to the device, (4) need for revision of device or leads due to lead migration or failure, (5) development of hydronephrosis.

Inclusion Criteria (to be part of the study):

Exclusions (things that would exclude you from being a participant of the study):