Bradley C. Gill

Dual Simulated Childbirth Injuries Result in Slowed Recovery of Pudendal Nerve and Urethral Function

Pelvic floor muscle trauma and pudendal nerve injury have been implicated in stress urinary incontinence (SUI) development after childbirth. In this study, we investigated how combinations of these injuries affect recovery.

Rat mesenchymal stem cell secretome promotes elastogenesis and facilitates recovery from simulated childbirth injury.

Vaginal delivery is a risk factor for stress urinary incontinence (SUI). Mesenchymal stem cells (MSCs) home to injured organs and can facilitate repair. The goal of this study was to determine if MSCs home to pelvic organs after simulated childbirth injury and facilitate recovery from SUI via paracrine factors. Three experiments were performed. Eighteen female rats received vaginal distension (VD) or sham VD and labeled intravenous (IV) MSCs to investigate if MSCs home to the pelvic organs. Whole-organ imaging and immunofluorescence were performed 1 week later. Thirty-four female rats received VD and IV MSCs, VD and IV saline, or sham VD and IV saline to investigate if MSCs accelerate recovery of continence. Twenty-nine female rats received VD and periurethral concentrated conditioned media (CCM), VD and periurethral control media, or sham VD and periurethral control media to investigate if factors secreted by MSCs accelerate recovery from VD. Urethral histology and function were assessed 1 week later. Significantly more MSCs were observed in the urethra, vagina, and spleen after VD compared to sham VD. Continence as measured by leak point pressure (LPP) was significantly reduced after VD in rats treated with saline or control media compared to sham VD but not in those given MSCs or CCM. External urethral sphincter (EUS) function as measured by electromyography (EMG) was not improved with MSCs or CCM. Rats treated with MSCs or CCM demonstrated an increase in elastin fibers near the EUS and urethral smooth muscle more similar to that of sham-injured animals than rats treated with saline or control media. MSCs homed to the urethra and vagina and facilitated recovery of continence most likely via secretion of paracrine factors. Both MSCs and CCM have promise as novel noninvasive therapies for SUI.

Neurogenic aspects of stress urinary incontinence

Purpose of review Vaginal childbirth is a significant risk factor for stress urinary incontinence (SUI). Women with SUI demonstrate dysfunction of the pelvic floor and pudendal nerve. Animal models of SUI have been developed to investigate its pathophysiology and for preclinical testing of potential treatments. Recent findings Vaginal distension, a method of simulating childbirth injury in animals, produces a reliable decrease in leak point pressure (LPP), a measure of urethral resistance to leakage and quantification of SUI severity in animals. In addition to ischemia and direct tissue damage, vaginal distension causes denervation of the external urethral sphincter (EUS). Pudendal nerve crush produces a similar decrease in LPP, whereas combined PNC and vaginal distension injury delays recovery of LPP compared with either single injury alone. Neurophysiologic studies have elucidated the results of each injury and their combination on pudendal nerve and EUS function. Urethrolysis, electrocautery, and pudendal nerve transection produce more durable functional impairment via both structural damage and denervation. Pubourethral ligament injury eliminates the structural support of the urethra, but its neurologic effects are unknown. Summary Animal models demonstrate a complex interplay between tissue damage and pudendal nerve dysfunction, and provide insight into the importance of neuroregeneration in the recovery of continence.

Risk of Infection After Midurethral Synthetic Sling Surgery: Are Postoperative Antibiotics Necessary?

OBJECTIVES To review our postoperative infections using single-dose preoperative antibiotics. Midurethral synthetic sling surgery is commonly performed. Postoperative antibiotics are often prescribed and may have some risk of adverse events (AEs). We are unaware of data suggesting decreased risk of infection with this practice. METHODS We reviewed all midurethral synthetic sling surgery charts from 2004 to 2008 performed by 1 surgeon who uses only single-dose preoperative antibiotics (controls), and 2 who also use postoperative antibiotics(cases). A telephone survey was administered, which included questions regarding postoperative infections and AEs related to antibiotic use. Our primary and secondary outcomes were urinary tract infections (UTIs) and AEs related to antibiotic use, respectively. Patients were excluded for bladder injuries, postoperative catheters, and concomitant prolapse surgery. RESULTS We identified 103 cases and 116 controls, and the telephone survey response rate was 81.3%. At baseline, groups had similar characteristics. There was no significant difference in UTIs between cases (6.8%) and controls (9.5%). There were no skin infections. AEs related to antibiotic use were more common among those that received postoperative antibiotics (7.8% vs 0.9%, P=.03). There were 5 (63%) yeast infections, 1 (12.5%) rash, 1 (12.5%) case of nausea, and 1 (12.5%) patient with colitis among cases and 1 yeast infection among controls. CONCLUSIONS UTI is common after sling surgery, but other infections are rare. The occurrence of UTI does not appear to be lower when postoperative antibiotics are prescribed. However, AEs associated with antibiotic use are increased. These findings do not support the use of postoperative antibiotics.

Increasing Patient Preparedness for Sacral Neuromodulation Improves Patient Reported Outcomes Despite Leaving Objective Measures of Success Unchanged

PURPOSE We assessed how a group shared appointment influenced patient preparedness for sacral nerve stimulation for refractory overactive bladder and/or urge urinary incontinence. We also evaluated subjective and objective outcomes. MATERIALS AND METHODS Patients considering sacral nerve stimulation were prospectively enrolled and invited to attend a group shared appointment. This 75-minute presentation included a question and answer period with an implanting surgeon and an implanted patient. Control patients received standard office counseling. A patient preparedness questionnaire was completed after the group shared appointment or office counseling. Response to treatment was determined using the postoperative satisfaction questionnaire, Patient Global Impression of Improvement (PGI-I) and voiding diaries. RESULTS In our study 36 women with a mean ± SD age of 61 ± 15 years underwent sacral nerve stimulation. There was no significant difference in patient demographics between the 19 women who attended the group shared appointment and the 17 controls. Overall preparedness was greater in the shared appointment group (p = 0.043) with better understanding of the purpose of (p = 0.003) and alternatives to (p = 0.043) sacral nerve stimulation. Significantly more women in the shared appointment group than controls felt completely prepared (78.9% vs 29.4%, p = 0.003) and completely satisfied (78.9% vs 35.3%, p = 0.003) with sacral nerve stimulation as well as very much better (68.4% vs 17.6%, p = 0.002) according to the PGI-I. There was no difference between the groups in the number of women with a 50% or greater symptom reduction on voiding diary. CONCLUSIONS Participating in a group shared appointment before sacral nerve stimulation improved patient preparedness and perceived outcomes of treatment, although there was no difference in objective outcomes based on voiding diary.

Effects of acute selective pudendal nerve electrical stimulation after simulated childbirth injury

During childbirth, a combinatorial injury occurs and can result in stress urinary incontinence (SUI). Simulated childbirth injury, consisting of vaginal distension (VD) and pudendal nerve crush (PNC), results in slowed recovery of continence, as well as decreased expression of brain-derived neurotrophic factor (BDNF), a regenerative cytokine. Electrical stimulation has been shown to upregulate BDNF in motor neurons and facilitate axon regrowth through the increase of β(II)-tubulin expression after injury. In this study, female rats underwent selective pudendal nerve motor branch (PNMB) stimulation after simulated childbirth injury or sham injury to determine whether such stimulation affects bladder and anal function after injury and whether the stimulation increases BDNF expression in Onufs nucleus after injury. Rats received 4 h of VD followed by bilateral PNC and 1 h of subthreshold electrical stimulation of the left PNMB and sham stimulation of the right PNMB. Rats underwent filling cystometry and anal pressure recording before, during, and after the stimulation. Bladder and anal contractile function were partially disrupted after injury. PNMB stimulation temporarily inhibited bladder contraction after injury. Two days and 1 wk after injury, BDNF expression in Onufs nucleus of the stimulated side was significantly increased compared with the sham-stimulated side, whereas β(II)-tubulin expression in Onufs nucleus of the stimulated side was significantly increased only 1 wk after injury. Acute electrical stimulation of the pudendal nerve proximal to the crush site upregulates BDNF and β(II)-tubulin in Onufs nucleus after simulated childbirth injury, which could be a potential preventive option for SUI after childbirth injury.

Neurotrophin therapy improves recovery of the neuromuscular continence mechanism following simulated birth injury in rats

Stress urinary incontinence (SUI) affects women both acutely and chronically after vaginal delivery. Current SUI treatments assume the neuromuscular continence mechanism, comprised of the pudendal nerve (PN) and external urethral sphincter (EUS), is either intact or irreparable. This study investigated the ability of neurotrophin therapy to facilitate recovery of the neuromuscular continence mechanism.

Pudendal Nerve Stretch Reduces External Urethral Sphincter Activity in Rats

PURPOSE Most animal models of stress urinary incontinence simulate maternal injuries of childbirth since delivery is a major risk factor but they do not reproduce the nerve stretch known to occur during human childbirth. We hypothesized that pudendal nerve stretch produces reversible dysfunction of the external urethral sphincter. MATERIALS AND METHODS Female virgin Sprague-Dawley® rats were anesthetized with urethane. Bilateral pudendal nerve stretch or sham injury was performed for 5 minutes. External urethral sphincter electromyography and leak point pressure were recorded immediately before and after, and 10, 30, 60 and 120 minutes after pudendal nerve stretch. Post-pudendal nerve stretch results were compared to prestretch values and to values in sham injured animals. The pudendal nerves underwent qualitative histological assessment. The nucleus of Onuf was evaluated by immunohistochemistry and polymerase chain reaction for β-APP and c-Fos expression as markers of neuronal activity and injury. RESULTS A total of 14 rats underwent bilateral pudendal nerve stretch (9) or sham injury (5). Each nerve was stretched a mean ± SEM of 74% ± 18% on the left side and 63% ± 13% on the right side. Electromyography amplitude decreased significantly immediately after stretch compared to before stretch and after sham injury (p = 0.003) but it recovered by 30 minutes after stretch. There was no significant change in leak point pressure at any time. Two hours after injury histology showed occasional neuronal degeneration. β-APP and c-Fos expression was similar in the 2 groups. CONCLUSIONS Acute pudendal nerve stretch produces reversible electrophysiological dysfunction but without leak point pressure impairment. Pudendal nerve stretch shows promise in modeling injury. It should be tested as part of a multi-injury, chronic, physiological model of human childbirth injury.

Future Perspectives in Bladder Tissue Engineering

Substantial clinical need persists for improved autologous tissues to augment or replace the urinary bladder, and research has begun to address this using tissue engineering techniques. The implantation of both tissue scaffolds, which allow for native bladder tissue ingrowth, and autologous bladder grafts created from in-vitro cellularization of such scaffolds have been tested clinically; however, successful outcomes in both scenarios have been challenged by insufficient vascularity resulting from large graft sizes, which subsequently limits tissue ingrowth and leads to central graft ischemia. Consequently, recent research has focused on developing better methods to produce scaffolds with increased tissue ingrowth and vascularity. This review provides an update on bladder tissue engineering and outlines the challenges that remain to clinical implementation.

Patterns of Hardware Related Electrode Failures in Sacral Nerve Stimulation Devices

PURPOSE Abnormal electrical impedance in sacral nerve stimulation devices is a cause of device failure. Currently, there is scant literature evaluating the incidence and management of this problem. We evaluated the presentation, characteristics and management of sacral nerve stimulation devices with abnormal electrical impedance. MATERIALS AND METHODS A total of 565 patients were permanently implanted with sacral nerve stimulation devices using a tined lead between 2003 and 2011. Devices were interrogated postoperatively and at followup. Abnormal electrical impedance was classified as open circuit--impedance greater than 4,000 Ω or short circuit--impedance less than 50 Ω and/or equivalence of impedance. Details on presentation, characteristics and management were recorded. RESULTS Of the 565 patients 72 (12.7%) experienced a total of 86 abnormal electrical impedance events, of which 57 (66.2%) were open circuits and 28 (32.5%) were short circuits. One event (1.1%) was a simultaneous open and short circuit. Short circuits presented earlier than open circuits (median 3.5 months, IQR 2-7.5 vs 15, IQR 5.5-30.5, p <0.0001) and required surgical intervention more often (75.0% vs 54.3%, p = 0.09). Patient specific factors, such as trauma history and change in body mass index class, were not associated with abnormal electrical impedance. No electrode failure patterns could be identified. CONCLUSIONS Abnormal electrical impedance occurred in approximately 13% of cases permanently implanted in our series. Short circuits presented earlier and often required surgical intervention. Open circuits presented later and may have potentially been secondary to microfractures that accumulate with time at the sacral plate, resulting in later presentation. Almost a third of patients with abnormal electrical impedance associated with clinical inefficacy were treated conservatively, primarily with reprogramming.