|580||Electrical Stimulation of Anal Sphincter or Pudendal Nerve Improves Anal Sphincter Pressure[2012.12 DCR]||2013-07-17||5341|
December 2012 - Volume 55 - Issue 12 - p 1284–1294
1 Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio
2 Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio
3 Advanced Platform Technology Center, Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio
4 Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio
5 American Medical Systems Inc., Minnetonka, Minnesota
6 Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio
Funding/Support: This research was supported in part by American Medical Systems, The Cleveland Clinic Foundation, and the Rehabilitation Research & Development Service of the Department of Veterans Affairs.
Financial Disclosure: Dr Damaser acted as a consultant to American Medical Systems in 2008 when this work was performed.
Correspondence: Massarat Zutshi, M.D., Cleveland Clinic Foundation, 9500 Euclid Ave, A30, Cleveland, OH 44195. E-mail: firstname.lastname@example.org
OBJECTIVE: Stimulation of the pudendal nerve or the anal sphincter could provide therapeutic options for fecal incontinence with little involvement of other organs. The goal of this project was to assess the effects of pudendal nerve and anal sphincter stimulation on bladder and anal pressures.
DESIGN: Ten virgin female Sprague Dawley rats were randomly allocated to control (n = 2), perianal stimulation (n = 4), and pudendal nerve stimulation (n = 4) groups. A monopolar electrode was hooked to the pudendal nerve or placed on the anal sphincter. Aballoon catheter was inserted into the anus to measure anal pressure, and a catheter was inserted into the bladder via the urethra to measure bladder pressure. Bladder and anal pressures were measured with different electrical stimulation parameters and different timing of electrical stimulation relative to spontaneous anal sphincter contractions.
RESULTS: Increasing stimulation current had the most dramatic effect on both anal and bladder pressures. An immediate increase in anal pressure was observed when stimulating either the anal sphincter or the pudendal nerve at stimulation values of 1 mA or 2 mA. No increase in anal pressure was observed for lower current values. Bladder pressure increased at high current during anal sphincter stimulation, but not as much as during pudendal nerve stimulation. Increased bladder pressure during anal sphincter stimulation was due to contraction of the abdominal muscles.
CONCLUSION: Electrical stimulation caused an increase in anal pressures with bladder involvement only at high current. These initial results suggest that electrical stimulation can increase anal sphincter pressure, enhancing continence control.
Fecal incontinence is a debilitating condition that often occurs in conjunction with urinary incontinence.1,2 It affects both men and women, but it is more common among women because of childbirth injury resulting from an episiotomy, stretch injury to the anal sphincter, and/or pudendal nerve injury.3,4
Neuromodulation has been used to stimulate the periurethral musculature and anal sphincter via the sacral nerve routes as they emerge from the spinal canal.5,6 Sacral nerve stimulation is approved by the US Food and Drug Administration for urinary incontinence6,7 and recently for fecal incontinence.8–11 A small study in urinary incontinence compared sacral and pudendal stimulation and found that patients preferred pudendal stimulation.12 Additionally, a recent study demonstrated that a small number of patients with fecal incontinence in whom sacral nerve stimulation failed improved with pudendal nerve stimulation, although this must be studied with a larger sample size.13
Stimulation of the pudendal nerve or of the anal sphincter for fecal incontinence has been recently investigated.13 Pudendal nerve stimulation could provide anal sphincter contraction without involvement of other organ systems. Either stimulation type could potentially provide an efficient method of increasing anal sphincter pressure. The objective of this study was to investigate the effects on anal sphincter and bladder pressures after electrical stimulation of the pudendal nerve or the anal sphincter in female rats.
The experimental protocol was approved by the Institutional Animal Care and Use Committee of the Cleveland Clinic. Ten virgin Sprague Dawley rats (240–260 g) were randomly allocated into 3 groups: control (n = 2), anal sphincter stimulation (n = 4), and pudendal nerve stimulation (n = 4). Anal sphincter function was assessed according to previously described methods.12 Under intraperitoneal anesthesia with ketamine (100 mg/kg) and xylazine (10 mg/kg), a small balloon (Kent Scientific, Torrington, CT; size 4, diameter 4 mm) attached to a water-filled catheter (PE-90 tubing, inside diameter 86 mm, outside diameter 1.27 mm) was pressurized and shallowly inserted into the rat’s rectum. Balloon pressure was referenced to zero at the level of the anus. Anal pressures were then measured continuously throughout the experiment via the catheter with the use of a pressure transducer (Grass Astromed, PT300, Warwick, RI) connected to an amplifier (Astromed Inc, model P-122/ and digital data recording system (Dash 8x, Astromed Inc) as in our previous study.12 Anal pressure recordings were analyzed with the use of Astroview X software (Astromed Inc, version 1.3) for differences in amplitude before and after electrical stimulation.
Bladder pressure was recorded simultaneously with anal sphincter pressures via a saline-filled catheter (PE-50 tubing, inside diameter 0.58 mm, outside diameter 0.965 mm) transurethrally.14 The bladder was filled at 5 mL/h with room-temperature saline via the urethral catheter. Bladder pressure recordings were similarly analyzed for differences in amplitude and characteristic shape before and after electrical stimulation. Control animals were anesthetized for the same time as experimental animals but underwent no stimulation.
Direct electrical stimulation of the anal sphincter was performed by using a monophasic signal on 4 animals via platinum needle electrodes (Grass, Warwick, RI; 12 mm, 30 gauge) placed shallowly into the anal sphincter muscle bilaterally without disturbing the abdominal musculature. Electrical stimulation of the pudendal nerve was performed on 4 animals with the use of bent platinum electrodes (0.8 mm distance between poles, 0.25 mm diameter, PB AD08100; FHC, Bowdoin, ME) hooked directly on the nerve as it traverses the ischiorectal fossa, distal to the branching of the pudendal nerve at the sciatic notch and proximal to the location where the pudendal nerve branches into many fine nerves. The anode and cathode for each pair were placed in close proximity. To obtain access to the pudendal nerve, the ischiorectal fossa was dissected bilaterally and accessed from the ventral side after opening the abdominal muscle and pubic symphysis (Fig 1).14 In our preliminary studies, we found little to no difference in the response to biphasic and monophasic stimulation. Therefore, for pudendal nerve stimulation, we used bilateral monophasic stimulation.
FIGURE 1. Illustration of the anatomy of the pudendal nerve in a rat. A, Sacral plexus containing pudendal nerve. * = the location of electrodes hooking the pudendal canal which contains both sensory and motor branches of the pudendal nerve. B, Ventral view of the stimulation location for the pudendal nerve in a female rat (ischiorectal fossa opened after separating pubic symphysis). C, The boxed area in B is enlarged to demonstrate the pudendal canal.
Three experiments were performed on each animal. The first investigated the effect of varying current, pulse duration, frequency, and duration of stimulation on bladder and anal pressures during baseline pressure recordings between spontaneous anal sphincter contractions. Four current levels (0.25, 0.5, 1.0, and 2.0 mA), 3 stimulus durations (1.0, 5.0, and 10.0 seconds), 3 frequencies (20, 30, and 40 Hz), and 3 pulse durations (50, 75, and 100 μs) were investigated with both anal sphincter and pudendal nerve stimulation.
Testing of all possible combinations of these variables would have required 108 stimulations in each animal; which could fatigue the anal sphincter and reduce the reliability of the results. Therefore, D-optimal design15,16 construction was used to identify 12 experimental combinations that would permit an investigation of the linear and curvilinear effects of changes in current, duration, frequency, and pulse duration. These 12 stimulations were performed twice in randomized order in each animal.
A second experiment was performed in the same animals to investigate the effects of timing of stimulation relative to spontaneous anal sphincter contractions. Electrical stimulation was randomly initiated at the beginning, middle, and end of a spontaneous contraction and between spontaneous contractions (Fig. 2). The timing of stimulation was obtained from anal pressure recordings in unstimulated animals and experience from our previous studies,12,17 which showed spontaneous anal contractions that were very consistent. Stimulation was performed with the stimulating needle in place while viewing the anal contractions on the recorder in real time.
To determine whether abdominal muscle contraction from anal sphincter stimulation contributed to the rise in bladder pressure, electrical stimulation of the anal sphincter was performed before and after abdominal muscle transection which reduces intraperitoneal pressure to zero. A high current value (4 mA) that would produce a bladder pressure response to stimulation was used in this experiment with 20 Hz, 100 µs pulse duration, and 5 seconds duration stimulation.
To determine whether the effects of pudendal nerve stimulation were due to signal transmission via the pudendal nerve or to spread of the electrical signal via surrounding tissues, the same stimulation settings were used as above 3 times before and 3 times after bilateral pudendal nerve transection proximal to the stimulating electrode. The pudendal nerve was then transected distal to the electrode, leaving a small isolated piece of pudendal nerve sitting across the bipolar electrode, which was stimulated, and pressures were recorded.
The changes in anal and bladder baseline and contraction pressures with stimulation were calculated. Because anal pressure contained spontaneous contractions, the maximum, minimum, and mean changes in pressure were calculated for anal sphincter pressure during spontaneous contractions. The average value of each variable at each setting for each animal was obtained and used to create a group mean that was used for statistical comparisons.
To determine the effect of varying electrical stimulation parameters, each outcome was analyzed by using linear regression, and the results were summarized in the form of a regression equation relating significant variables to the measured response, with p < 0.05 indicating a statistically significant difference. To determine the effect of timing of stimulation, each outcome was analyzed by using a 1-way ANOVA, followed by a Tukey-Kramer post hoc pairwise means comparison, with p < 0.05 indicating a statistically significant difference. Change in anal sphincter or bladder pressure resulting from changing each stimulation variable is expressed as mean ± SEM of data from 4 animals.
There was no significant change in anal sphincter or bladder pressure in control animals while they were anesthetized.
Effect of Varying Stimulation Parameters
Increasing the current had the most dramatic effect on both anal and bladder pressures of all stimulation variables tested. Anal pressure increased significantly during 1- or 2-mA stimulation of either the anal sphincter or pudendal nerve. In contrast, there was little to no increase in anal pressure observed during 0.5- or 0.25-mA stimulation. Increased current significantly increased the maximum (2.9 ± 0.4 cm H2O, p < 0.001), minimum (1.0 ± 0.5 cm H2O, p = 0.046), and average (2.6 ± 0.3 cm H2O, p < 0.001) change in anal sphincter pressure with both anal sphincter and pudendal nerve stimulation (Fig. 3).
FIGURE 3. Phase plots showing the effect of change of current, pulse duration, and frequency on anal contraction pressures. A, Increased anal sphincter contraction pressure with anal sphincter stimulation occurs with increase in both current and frequency. B, Increase in anal sphincter contraction pressure with pudendal nerve stimulation occurs with increase in current alone. Increase in anal sphincter baseline pressure with anal sphincter stimulation occurs with increase in current as well as pulse duration and frequency. The data shown are at frequency of 20 Hz (C) and 40 Hz (D). E, Increase in bladder pressure with anal sphincter stimulation occurs with increase in current and pulse duration. F, Increase in bladder pressure with pudendal nerve stimulation occurs with increase in current and pulse duration.
Increasing frequency significantly decreased the maximum change in anal sphincter pressure (0.8 ± 0.4 cm H2O, p = 0.047) during anal sphincter stimulation only (Fig. 3A). Anal sphincter baseline pressure also increased significantly with increased current (0.7 ± 0.3 cm H2O, p = 0.04) and changed nonlinearly with increased frequency (–1.3 ± 0.6 cm H2O, p = 0.04; Figs. 3C and D). The maximum (–1.0 ± 0.4 cm H2O, p = 0.005), minimum (0.7 ± 0.3 cm H2O, p = 0.008), and average (1.8 ± 0.3 cm H2O, p < 0.0001) change in anal sphincter baseline pressure due to anal sphincter stimulation decreased significantly with increases in pulse duration (Fig. 3C). The minimum change in anal sphincter baseline pressure due to nerve stimulation decreased (4.4 ± 0.1 cm H2O, p < 0.001) with increasing duration of stimulation, whereas the average change in anal sphincter baseline pressure due to nerve stimulation decreased with increases in current.
Because stimulation was timed to occur between anal sphincter contractions, increases in bladder pressure directly related to stimulation were difficult to demonstrate, because spontaneous bladder contractions were not consistently timed with stimulation. Nonetheless, maximal change in bladder pressure due to either anal sphincter or pudendal nerve stimulation was significantly increased by increases in both current (9.7 ± 3.4 cm H2O, p = 0.001) and pulse duration (5.5 ± 1.2 cm H2O, p < 0.001; Figs. 3E and F). Average change in bladder pressure due to pudendal nerve stimulation was also significantly increased by increases in current (3.8 ± 0.9 cm H2O, p = 0.001), pulse duration (1.9 ± 0.7 cm H2O, p = 0.01), and frequency. There were no significant effects on baseline bladder pressure due to either anal sphincter or pudendal nerve stimulation.
Effect of Varying Timing of Stimulation
A noticeable increase in anal pressure was observed with all stimulations regardless of timing, although this could be difficult to discern when stimulation was performed during a spontaneous anal sphincter contraction (Fig. 4). Bladder pressure was also relatively responsive to electrical stimulation; however, the changes in bladder pressure were not significantly dependent on the timing of stimulation relative to anal sphincter contraction with either anal sphincter or pudendal nerve stimulation, demonstrating the independence of spontaneous bladder and anal sphincter contractions (Fig. 4).
Figure FIGURE 4. Example of the anal sphincter (dotted line) and bladder (solid line) pressure before, during, and after electrical stimulation of the anal sphincter (A, B) and pudendal nerve (C, D) during the experiment to assess the effect of varying the timing of stimulation. Stimulation was performed between (A), at the end (B), at the beginning (C), and in the middle (D) of a spontaneous anal sphincter contraction. Stimulation parameters consisted of 2 mA, 30 Hz, and 100 μs pulse duration and were of 10 seconds duration. The thick horizontal bar indicates timing and duration of stimulation. Stimulation settings for each example are given above the graph. ma = current (mA); pps = frequency (Hz); s = duration (seconds); us = pulse duration (µsec).
The increase in anal sphincter pressure was significantly greater if anal sphincter stimulation was initiated at the beginning of a spontaneous anal sphincter contraction than if it was initiated at the end of a spontaneous anal sphincter contraction (Fig. 5). The minimal increase in anal sphincter pressure was significantly greater if anal sphincter stimulation was initiated in the middle of a spontaneous anal sphincter contraction (31.8 ± 3.7 cm H2O) than if it was initiated at the end of a spontaneous anal sphincter contraction (20.5 ± 3.7 cm H2O, p = 0.003; Fig. 5). Anal sphincter stimulation initiated at the end of a spontaneous contraction caused on average a small decrease in minimum anal sphincter pressure relative to baseline values. This was not typical of anal sphincter stimulation initiated at any other time relative to spontaneous anal sphincter contractions. Maximal, minimal, and average baseline anal sphincter pressure increased significantly with anal sphincter stimulation at the beginning of a spontaneous anal sphincter contraction in comparison with stimulation at the middle or end of a spontaneous anal sphincter contraction (Fig. 5).
Figure FIGURE 5. Anal sphincter pressure changes due to anal sphincter stimulation. Change in maximum (A), minimum (B), and average (C) anal sphincter spontaneous contraction pressure and maximum (D), minimum (E), and average (F) anal sphincter baseline pressure. * = a significant difference in comparison with stimulation at the end of anal sphincter contraction; + = a significant difference in comparison with stimulation in the middle of anal sphincter contraction. Each bar represents the mean ± SEM of data from 4 animals.
Both maximal and average increase in anal sphincter pressure were significantly greater if the pudendal nerve was stimulated at the beginning of a spontaneous anal sphincter contraction (maximum, 24.1 ± 2.8 cm H2O; average, 20.2 ± 3.1 cm H2O) than if it was stimulated at the end of a spontaneous anal sphincter contraction (maximum, 16.3 ± 2.8 cm H2O; average, 14.48 ± 3.1 cm H2O; Fig. 6). Similarly, nerve stimulation initiated at the end of a spontaneous anal sphincter contraction resulted in a small drop in anal sphincter pressure relative to baseline values. Average baseline anal sphincter pressure significantly increased if stimulation was initiated at the beginning (10.1 ± 3.0 cm H2O) of a spontaneous anal sphincter contraction in comparison with stimulation initiated at either the middle or end (20.7 ± 3.0 cm H20; p = 0.001; 16.0 ± 3.0 cm H2O, p = 0.03). Both maximal (20.2 ± 3.1 cm H2O) and minimal (12.8 ± 2.8 cm H2O) anal sphincter pressure significantly decreased if stimulation was initiated at the end of a spontaneous anal sphincter contraction in comparison with stimulation initiated at the beginning of a spontaneous contraction (p < 0.05; Fig. 6).
Figure FIGURE 6. Anal sphincter pressure changes due to pudendal nerve stimulation. Change in maximum (A), minimum (B), and average (C) anal sphincter spontaneous contraction pressure and maximum (D), minimum (E), and average (F) anal sphincter baseline pressure. * Indicates a significant difference in comparison with stimulation at the end of anal sphincter contraction. + Indicates a significant difference in comparison with stimulation in the middle of anal sphincter contraction. Each bar represents the mean ± SEM of data from 4 animals. Back to Top | Article Outline
Effect of Muscle and Nerve Transection
At the end of the anal sphincter stimulation studies, the anal sphincter was stimulated before and after the abdominal musculature was cut. Muscle transection resulted in a significant decrease (to zero) of the bladder pressure response to anal sphincter stimulation, indicating that the increase in bladder pressure from anal sphincter stimulation was due to increased pressure on the bladder from abdominal muscle contraction (Figs. 7A and B).
Figure FIGURE 7. Bladder (solid line) and anal sphincter (dashed line) pressure in response to anal sphincter stimulation before (A) and after (B) transecting abdominal muscles as well as in response to pudendal nerve stimulation before (C) and after (D) transecting the pudendal nerve distal to the stimulation. Muscle transection eliminated the increase in bladder pressure due to anal sphincter stimulation. Distal nerve transection eliminated the increase in anal sphincter pressure due to stimulation of the pudendal nerve. The thick horizontal bar indicates timing and duration of stimulation. Stimulation settings for each example are given above the graph. ma = current (mA); pps = frequency (Hz); s = duration (seconds); us = pulse duration (µsec); AS = anal sphincter stimulation; NS = pudendal nerve stimulation.
The pudendal nerve was stimulated before and after transecting the pudendal nerve proximal and then distal to the site of stimulation. Nerve transection proximal to the stimulating electrode did not alter bladder and anal pressure responses to pudendal nerve stimulation. Nerve transection distal to the stimulating electrode resulted in a significant decrease (to zero) of the anal sphincter pressure response to nerve stimulation (Figs. 7C and D), indicating that the effects of pudendal nerve stimulation were via transmission of the signal along the motor branch of the pudendal nerve rather than by reflex action or spread of signal to nearby tissues.
Incontinence to solid and liquid stool are the result of anal dysfunction, 18–20 which, in women, can often be attributed to direct anal sphincter laceration and repeat stretching of the pudendal nerve during childbirth.21 The current array of therapeutic options includes conservative treatment and surgical options.22 However, long-term results after sphincter repair are not satisfactory23,24 whereas sacral nerve stimulation has gained acceptance in selected patients.9–11,25 We investigated electrical stimulation as an alternative treatment for fecal incontinence.
There is some nonspecificity associated with stimulation of the sacral nerves demonstrated by the knowledge that sacral nerve stimulation affects not only fecal incontinence, but also urinary incontinence, urinary retention, constipation, and pain in the pelvic floor because of the combined effects on the central, sensory, and motor pathways.26 The pudendal nerve shares common sensory-motor innervation to the clitoris, urethra, and the striated muscle of the anal sphincter.27 Thus, it could potentially be used as a specific target when using electrical stimulation for fecal incontinence, limiting and focusing its effects to the lower urinary tract and anal sphincter without unwanted side effects. This study focused on anal sphincter and bladder pressure after stimulation of the pudendal nerve or the anal sphincter. Although increases in anal sphincter pressure have not been proven to indicate continence of stool, anal pressures reflect the strength of the anal sphincter and can be used as a functional surrogate for fecal incontinence.28,29 To this end, we investigated the effects of changing stimulation parameters and timing of stimulation on anal and bladder pressures.
Of all the parameters used in the study, current and frequency were identified as the parameters that had the greatest impact on anal and bladder pressures attributed to electric stimulation, as other studies of stimulation and in various organs have demonstrated previously.30–33 Anal sphincter stimulation required less current than pudendal nerve stimulation to generate similar responses, particularly at higher currents, perhaps because of the stimulation of nerve branches in the sphincter, the muscle itself, or the combination of the 2. In addition, anal sphincter stimulation generated less bladder pressure involvement, presumably because the anal sphincter stimulation electrodes were in direct contact with the muscle causing an immediate and strong anal sphincter contraction. When higher currents were used for anal sphincter stimulation, bladder pressure also increased. This was secondary to stimulation of abdominal muscles causing increased pressure on the bladder, as demonstrated by the lack of bladder response after transection of the abdominal muscles.
Electrical stimulation reliably resulted in changes in anal sphincter pressure, although changes were also noted in bladder pressure. Significant anal sphincter pressure increases were observed to achieve their greatest extent when stimulation was applied at the beginning of anal sphincter contraction. This could be the result of electric stimulation facilitating the spontaneous anal sphincter contraction that was already beginning.34 Stimulation at the end of a spontaneous anal sphincter contraction did not result in a significant increase in anal sphincter pressure, probably because, at the end of a muscle contraction, the closing of Na+ channels coupled with the opening of K+ channels makes muscle cells less responsive to the incoming electrical stimulus.35 Our results suggest that the timing of stimulation may be considered as an important factor for optimal stimulation of anal sphincter and restoration of fecal incontinence.
Few other investigators have measured anal sphincter pressures in experimental animals,35,36 and even fewer have investigated the effects of electrical stimulation on these pressures.37 We used rats in our experiment because of their availability and the extensive information available regarding the innervation and physiology of the anal sphincter in rats.12,17 However, rats are small, increasing the possibility of spread of the electrical stimulation to other tissues, particularly at higher currents. For this reason, we transected the pudendal nerve proximal and distal to the stimulating electrodes to investigate if the observed effects on anal sphincter and bladder pressure were due to current transmission along the pudendal nerve or via spread of the signal to other tissues. The increase in anal sphincter pressure was eliminated by transection of the pudendal nerve distal to the electrodes in all animals, demonstrating that the primary means of stimulation-activated signal transmission is via stimulation of the motor branch of the pudendal nerve, which innervates the anal sphincter,27 and that spread of the electrical signal had only a negligible effect.
We performed a similar experiment on animals undergoing anal sphincter stimulation by transecting the abdominal musculature to determine whether the increase in bladder contraction was due to contraction of abdominal muscles pressing on the bladder, rather than via direct stimulation of the bladder. Abdominal muscle transection eliminated the bladder pressure increase due to anal sphincter stimulation in all animals, indicating that, at high currents, stimulation spread from the anal sphincter to the abdominal muscles in these small experimental animals. For clinical utilization of direct anal sphincter stimulation, stimulation current values could be set below the threshold for abdominal muscle involvement.
The anesthesia used in this experiment could have affected bladder and anal sphincter pressures and may potentially not well represent these values in a conscious animal. We used a standard method of anesthetizing animals for physiological recordings, and we have previously demonstrated that this anesthetic successfully maintains spontaneous anal sphincter contractions.12,17 Because anesthesia is needed for measurement of anal sphincter pressure in rats, we included assessment of 2 control rats. These animals maintained consistent bladder and anal sphincter pressures throughout the anesthesia period, demonstrating that the effects observed in the experimental animals were not time dependent.
Animal models have been previously used to test new therapeutic options for both urinary and fecal incontinence.38–41 Although this study focuses on a short stimulation, continuous stimulation of the sacral nerve has been investigated both in animal models and clinical studies for both urinary and fecal incontinence.10,42–44 Furthermore, chronic pudendal nerve stimulation has been attempted with a small number of patients. 13 Therefore, chronic stimulation of the anal sphincter or pudendal nerve may be useful to investigate in the future both preclinically in chronic animal models and in clinical trials. Currently there is an interest in pursuing pudendal nerve stimulation as a therapeutic option, and this study could be the basis for future clinical research.