Urinary Bladder, Underactive
Conditions
Keywords
electrical stimulation, urodynamics, bladder, urethra
Brief summary
The purpose of this study is to determine the influence of intravesical (bladder) electrical stimulation and intraurethral electrical stimulation on bothersome symptoms and bladder function in neurologically-intact adult women with underactive bladder. The investigators hypothesize that electrical stimulation will decrease bothersome urinary symptoms relative to baseline and increase voided percentage during pressure-flow studies compared to their routine clinical exam.
Detailed description
1. Objective: The overall objective of this study is to improve lower urinary tract symptoms (LUTS) in adult neurologically-intact women with underactive bladder through electrical stimulation of bladder sensory nerves or urethral sensory nerves. 2. Background and Significance: The storage and elimination of urine is regulated by neural circuits in the brain and spinal cord to coordinate function between the urinary bladder and the urethra. During micturition (bladder emptying), the elimination of urine is facilitated by bladder muscle (detrusor) contraction and urethral and pelvic floor muscle relaxation. Urine flow through the urethra also activates sensory nerves to amplify bladder contractions and maintain efficient bladder emptying. Incomplete emptying and urinary retention occur when these mechanisms are disrupted or poorly coordinated. Incomplete emptying due to underactive bladder is a poorly understood health concern that symptomatically affects up to 40% of the population, with the highest prevalence of symptoms in older men and women. Despite the high prevalence of symptoms, the diagnosis of an underactive bladder remains low due to the lack of consistent terminology and standardized diagnostic criteria. This results in defining underactive bladder by a symptom complex that may involve reduced motor drive (detrusor underactivity) during bladder emptying and/or reduced sensory drive during filling and emptying. Symptoms experienced by persons with underactive bladder include nocturia, urinary frequency, urgency, incontinence, slow stream, hesitancy, straining, and sensation of incomplete emptying. The most common symptoms are nocturia, slow stream, frequency, hesitancy, and the impact of these symptoms on quality of life is substantial for many patients. The management options for persons with underactive bladder include double-void, intermittent self-catheterization, or pharmacotherapy. However, these treatments are associated with poor quality of life and patients often fail to completely resolve the lower urinary tract symptoms (LUTS). There is a need to clarify the pathological mechanisms underlying underactive bladder to improve therapeutic outcomes. One approach to clarify reduced sensory drive is to evaluate the functional integrity of sensory nerves with quantitative sensory testing. Current perception threshold (CPT) testing delivers electrical stimulation to activate nerve fibers that evoke sensory perception, and changes in bladder sensory pathways were demonstrated in persons with diabetic detrusor underactivity. These diagnostic tests, however, have not been applied to neurologically intact adult women with underactive bladder and may provide insight into pathological sensory dysfunction. The proposed research will quantify sensory nerve sensitivity in the bladder and urethra in adult women with underactive bladder. The investigators will then amplify sensory nerve activity via continuous electrical stimulation to improve LUTS associated with underactive bladder. Achieving the proposed objectives will establish a prognostic marker for rationally guided electrical stimulation in women with underactive bladder. Understanding how these mechanisms contribute to impaired emptying in underactive bladder will enable the development of novel therapeutics to enhance quality of life. 3. Subject Recruitment: Established patients with underactive bladder will be identified by MaestroCare chart review. New patients with underactive bladder will be identified by Duke urogynecologists who see patients at one of two urogynecologic offices (Navaho Clinic in Raleigh or Patterson Place in Durham). 4. Design and Procedures: The investigators will perform a parallel interventional study with two non-randomized study arms (bladder stimulation and urethral stimulation). Potential participants will be screened remotely by email via RedCap by completing a questionnaire to determine bothersome symptoms and perceptions of bladder function. Potential participants that meet eligibility criteria will be scheduled for an in person study procedure visit, where informed consent will be signed. Participants will then undergo current perception threshold (CPT) testing, where electrical stimulation will be delivered via a catheter to the urethra (intraurethral) and bladder (intravesical) to evoke sensation. The CPT results will inform whether the participant receives an investigational session of intravesical (bladder) electrical stimulation or intraurethral electrical stimulation. Following electrical stimulation, the participant will undergo urodynamic studies (cystometrogram, pressure-flow study) to assess bladder function after the investigational stimulation procedures. The participant will also be asked to complete remotely by email a post-study symptom RedCap questionnaire 7 days after study completion.
Interventions
DEVICENeurometer Neurotron CPT
All participants will undergo CPT testing. A Neurotron catheter (12-French) with electrode will be inserted through the urethra into the bladder. The catheter balloon will be inflated and positioned at the urethrovesical junction to stimulate the urethra 10-14 mm from the bladder neck. For bladder stimulation, the catheter balloon will be deflated and the catheter will be advanced into the bladder. The device will deliver sine wave stimulus pulses at 5, 250, and 2,000 Hz. CPT will be established using an automated forced choice paradigm by the method of levels. Testing order of the bladder and urethra will be randomized between participants.
PROCEDURECystometry
After bladder stimulation or during intraurethral stimulation, cystometry will be performed to assess bladder sensation and storage. A dual-chamber 8-French catheter will be passed through the urethra into the bladder for retrograde filling. A second 8-French catheter will be placed in the vagina to measure intra-abdominal pressure. A stimulation electrode catheter will only be inserted in the intraurethral stimulation arm. EMG pads will then be placed at 3 and 9 o'clock on each side of the perineum. The bladder will then be filled with room-temperature sterile saline solution in a retrograde fashion using a pump. Bladder sensation and urgency will be assessed while filling.
PROCEDUREPressure-flow study
A pressure flow study will be performed to evaluate voiding function after stimulation. The transurethral and intra-vaginal catheters are left in place after cystometry and the participant will be asked to void around them, into a commode. Bladder and abdominal pressures will be recorded, as well as urine flow over time.
Sponsors
Duke University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Females ages 18 and older * Able to provide informed consent and agree to the study risks * Willing to withdraw from medications affecting urination for the 48 hours prior to the procedure (e.g., alpha-adrenergic antagonists, cholinergic agonists, cholinesterase inhibitors) * Has the below response to 2 of the 3 questions: 1. Questions regarding self-reported poor sensation during bladder filling or emptying (one or more of the below) * In the past 7 days, where did the participant feel sensations when needing to urinate? Answer: No response for Bladder Area * In the past 7 days, how often did the participant have no sensation of urine flow while urinating? Answer: Most of the time or Every time response * In the past 7 days, how often did the participant feel that the bladder was not completely empty after urination? Answer: Most of the time or Every time response 2. Questions regarding self-reported bothersome urinary symptoms (one or more of the below) * In the past 7 days, how satisfied was the participant with bladder function? Answer: Not at all satisfied or Somewhat satisfied response * In the past 7 days, how bothered was the participant by urinary symptoms? Answer: Very bothered or Extremely bothered response 3. Standard uroflowmetry with a voiding efficiency (voided volume / voided volume + residual volume) of \< 80%, voided volume + residual volume must be \>150ml for measurement
Exclusion criteria
* Preexisting neurological impairment (e.g., spinal cord injury, multiple sclerosis, Guillain-Barre, cauda equina syndrome, cerebrovascular accident, Parkinson's disease, traumatic brain injury) * Functional obstruction demonstrated by either elevated pelvic floor activity on EMG during standard pressure flow study or high tone pelvic floor on clinical exam) * Pelvic organ prolapse beyond introitus * Active urinary tract infection (candidate would be deferred until treated) * Positive pregnancy test * Less than 6 weeks postpartum * Unevaluated hematuria * Urethral stricture/stenosis * Surgical obstruction i.e., urinary retention due to obstructive sling or other anti incontinence procedure * Surgical procedures to increase bladder capacity (e.g., augmentation cystoplasty) * Active sacral neuromodulation or ongoing posterior tibial nerve stimulation sessions * Botulinum toxin injection in the past six months * History of genitourinary or gastrointestinal cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Voiding Efficiency | Baseline, pressure-flow study (up to 60 minutes) | Use of intraurethral electrical stimulation or intravesical electrical stimulation to assess increase in voided percentage during pressure-flow studies. Voiding efficiency is calculated as voided volume divided by the sum of voided volume and residual volume. |
| Change in Bothersome Symptoms and Sensation | baseline and post study procedures, up to 60 minutes | Lower Urinary Tract Dysfunction Research Network Symptom Index-29 (LURN SI-29) to assess whether electrical stimulation decreases urinary bothersome symptoms and increases bladder sensation during filling and emptying. Scores range from 0 (least severe) to 100 (most severe). Higher scores indicate greater severity of lower urinary tract symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Current Perception Threshold | CPT, up to 60 minutes | Assess bladder or urethral current perception threshold (CPT) in women with underactive bladder compared to normative values. The CPT value determined by the device is defined as the average of the minimum amplitude of the stimulus consistently detected and the stimulus 40 µA lower that was consistently not detected. |
| Cystometry Volume | cystometry before stimulation and after stimulation (up to 60 minutes) | Use of intravesical electrical stimulation to assess volumes during cystometry. Bladder sensation and urgency assessed at volume of first sensation during bladder filling, first desire to void, strong desire to void, and maximum cystometric capacity. |
| Bladder Contraction Strength | Baseline, pressure-flow study (up to 60 minutes) | Use of intraurethral electrical stimulation to assess contraction strength relative to baseline. Bladder pressure (cmH2O) is recorded over time during voiding. |
| Bladder Contraction Duration | Baseline, pressure-flow study (up to 60 minutes) | Use of intraurethral electrical stimulation to assess flow duration during a bladder contraction relative to baseline. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intravesical Electrical Stimulation To evaluate improvement of sensations during bladder filling and emptying with electrical stimulation to the bladder or urethra. The researchers will use the values obtained from investigational sensory testing to deliver continuous electrical stimulation to the bladder . The location depends on which value is higher compared to normal. A nurse or doctor will place a catheter with electrodes to perform this investigational study procedure to the bladder (up to 60 minutes). The researchers will also place a surface patch on the participant's abdomen to disperse the electrical current and reduce discomfort. | 12 |
| Intraurethral Electrical Stimulation To evaluate improvement of sensations during bladder filling and emptying with electrical stimulation to the bladder or urethra. The researchers will use the values obtained from investigational sensory testing to deliver continuous electrical stimulation to the urethra. The location depends on which value is higher compared to normal. A nurse or doctor will place a catheter with electrodes to perform this investigational study procedure to the urethra (up to 15 minutes). Two surface patches (electrodes) will be placed at the 3 o'clock and 9 o'clock positions, 1 to 3 centimeters from the around the vaginal opening. These electronic sensors will record muscle activity while the bladder is contracting.
The intraurethral stimulation will occur during routine urodynamic evaluation when the participant urinates on a special toilet. | 8 |
| Total | 20 |
Baseline characteristics
| Characteristic | Intravesical Electrical Stimulation | Total | Intraurethral Electrical Stimulation |
|---|---|---|---|
| Age, Continuous | 69 years STANDARD_DEVIATION 6 | 68 years STANDARD_DEVIATION 12 | 67 years STANDARD_DEVIATION 4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 19 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 17 Participants | 7 Participants |
| Region of Enrollment United States | 12 participants | 20 participants | 8 participants |
| Sex: Female, Male Female | 12 Participants | 20 Participants | 8 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 8 |
| other Total, other adverse events | 3 / 12 | 0 / 8 |
| serious Total, serious adverse events | 0 / 12 | 0 / 8 |
Outcome results
Primary
Change in Bothersome Symptoms and Sensation
Lower Urinary Tract Dysfunction Research Network Symptom Index-29 (LURN SI-29) to assess whether electrical stimulation decreases urinary bothersome symptoms and increases bladder sensation during filling and emptying. Scores range from 0 (least severe) to 100 (most severe). Higher scores indicate greater severity of lower urinary tract symptoms.
Time frame: baseline and post study procedures, up to 60 minutes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intravesical Electrical Stimulation | Change in Bothersome Symptoms and Sensation | Baseline | 52 CASUS questionnaire scores | Standard Deviation 15 |
| Intravesical Electrical Stimulation | Change in Bothersome Symptoms and Sensation | Post Study Procedures | 46 CASUS questionnaire scores | Standard Deviation 16 |
| Intraurethral Electrical Stimulation | Change in Bothersome Symptoms and Sensation | Baseline | 53 CASUS questionnaire scores | Standard Deviation 11 |
| Intraurethral Electrical Stimulation | Change in Bothersome Symptoms and Sensation | Post Study Procedures | 39 CASUS questionnaire scores | Standard Deviation 18 |
Comparison: Change from baseline to after the pressure-flow studyp-value: 0.08Mixed Models Analysis
Comparison: Change from baseline to after the pressure-flow studyp-value: 0.045Mixed Models Analysis
Primary
Voiding Efficiency
Use of intraurethral electrical stimulation or intravesical electrical stimulation to assess increase in voided percentage during pressure-flow studies. Voiding efficiency is calculated as voided volume divided by the sum of voided volume and residual volume.
Time frame: Baseline, pressure-flow study (up to 60 minutes)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intravesical Electrical Stimulation | Voiding Efficiency | Baseline | 32 voided percentage | Standard Deviation 31 |
| Intravesical Electrical Stimulation | Voiding Efficiency | Pressure-flow study (up to 60 minutes) | 43 voided percentage | Standard Deviation 37 |
| Intraurethral Electrical Stimulation | Voiding Efficiency | Baseline | 53 voided percentage | Standard Deviation 22 |
| Intraurethral Electrical Stimulation | Voiding Efficiency | Pressure-flow study (up to 60 minutes) | 46 voided percentage | Standard Deviation 27 |
Comparison: Change from baseline to after the pressure-flow studyp-value: 1Mixed Models Analysis
Comparison: Change from baseline to after the pressure-flow studyp-value: 0.99Mixed Models Analysis
Secondary
Bladder Contraction Duration
Use of intraurethral electrical stimulation to assess flow duration during a bladder contraction relative to baseline.
Time frame: Baseline, pressure-flow study (up to 60 minutes)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intravesical Electrical Stimulation | Bladder Contraction Duration | Baseline | 8 mL/s | Standard Deviation 3 |
| Intravesical Electrical Stimulation | Bladder Contraction Duration | Pressure-flow study (up to 60 minutes) | 15 mL/s | Standard Deviation 12 |
| Intraurethral Electrical Stimulation | Bladder Contraction Duration | Baseline | 15 mL/s | Standard Deviation 3 |
| Intraurethral Electrical Stimulation | Bladder Contraction Duration | Pressure-flow study (up to 60 minutes) | 13 mL/s | Standard Deviation 7 |
Comparison: Change from baseline to after the pressure-flow studyp-value: 1Mixed Models Analysis
Comparison: Change from baseline to after the pressure-flow studyp-value: 0.99Mixed Models Analysis
Secondary
Bladder Contraction Strength
Use of intraurethral electrical stimulation to assess contraction strength relative to baseline. Bladder pressure (cmH2O) is recorded over time during voiding.
Time frame: Baseline, pressure-flow study (up to 60 minutes)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intravesical Electrical Stimulation | Bladder Contraction Strength | Baseline | 11 cmH2O | Standard Deviation 32 |
| Intravesical Electrical Stimulation | Bladder Contraction Strength | Pressure-flow study (up to 60 minutes) | 21 cmH2O | Standard Deviation 18 |
| Intraurethral Electrical Stimulation | Bladder Contraction Strength | Pressure-flow study (up to 60 minutes) | 25 cmH2O | Standard Deviation 27 |
| Intraurethral Electrical Stimulation | Bladder Contraction Strength | Baseline | 33 cmH2O | Standard Deviation 41 |
Comparison: Change from baseline to after the pressure-flow studyp-value: 1Mixed Models Analysis
Comparison: Change from baseline to after the pressure-flow studyp-value: 1Mixed Models Analysis
Secondary
Current Perception Threshold
Assess bladder or urethral current perception threshold (CPT) in women with underactive bladder compared to normative values. The CPT value determined by the device is defined as the average of the minimum amplitude of the stimulus consistently detected and the stimulus 40 µA lower that was consistently not detected.
Time frame: CPT, up to 60 minutes
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intravesical Electrical Stimulation | Current Perception Threshold | 5 Hz | 8.57 mA (maximum amplitude) | Standard Deviation 3.23 |
| Intravesical Electrical Stimulation | Current Perception Threshold | 250 Hz | 9.99 mA (maximum amplitude) | Standard Deviation 0 |
| Intravesical Electrical Stimulation | Current Perception Threshold | 2000 Hz | 9.99 mA (maximum amplitude) | Standard Deviation 0 |
| Intraurethral Electrical Stimulation | Current Perception Threshold | 5 Hz | 8.27 mA (maximum amplitude) | Standard Deviation 3.61 |
| Intraurethral Electrical Stimulation | Current Perception Threshold | 250 Hz | 9.04 mA (maximum amplitude) | Standard Deviation 0.4 |
| Intraurethral Electrical Stimulation | Current Perception Threshold | 2000 Hz | 9.99 mA (maximum amplitude) | Standard Deviation 0 |
Secondary
Cystometry Volume
Use of intravesical electrical stimulation to assess volumes during cystometry. Bladder sensation and urgency assessed at volume of first sensation during bladder filling, first desire to void, strong desire to void, and maximum cystometric capacity.
Time frame: cystometry before stimulation and after stimulation (up to 60 minutes)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intravesical Electrical Stimulation | Cystometry Volume | first sensation of bladder filling - after stimulation | 281 mL | Standard Deviation 146 |
| Intravesical Electrical Stimulation | Cystometry Volume | maximum cystometric capacity - before stimulation | 517 mL | Standard Deviation 263 |
| Intravesical Electrical Stimulation | Cystometry Volume | maximum cystometric capacity - after stimulation | 528 mL | Standard Deviation 253 |
| Intravesical Electrical Stimulation | Cystometry Volume | first sensation of bladder filling - before stimulation | 290 mL | Standard Deviation 159 |
| Intraurethral Electrical Stimulation | Cystometry Volume | maximum cystometric capacity - after stimulation | 646 mL | Standard Deviation 211 |
| Intraurethral Electrical Stimulation | Cystometry Volume | first sensation of bladder filling - after stimulation | 357 mL | Standard Deviation 135 |
| Intraurethral Electrical Stimulation | Cystometry Volume | maximum cystometric capacity - before stimulation | 458 mL | Standard Deviation 225 |
| Intraurethral Electrical Stimulation | Cystometry Volume | first sensation of bladder filling - before stimulation | 253 mL | Standard Deviation 122 |
Comparison: First sensation of bladder filling - change in cystometry before stimulation and after stimulation (up to 60 minutes).p-value: 1Mixed Models Analysis
Comparison: First sensation of bladder filling - change in cystometry before stimulation and after stimulation (up to 60 minutes).p-value: 0.41Mixed Models Analysis
Comparison: Maximum cystometric capacity - change in cystometry before stimulation and after stimulation (up to 60 minutes).p-value: 1Mixed Models Analysis
Comparison: Maximum cystometric capacity - change in cystometry before stimulation and after stimulation (up to 60 minutes).p-value: 0.01Mixed Models Analysis