Contribution of Urethral Sensory Feedback in Voiding Efficiency
Condition: Urethral Anesthesia
Study type: Interventional

Summary: 
      The purpose of this study is to evaluate how urethral anesthesia impacts voiding efficiency
      in healthy women. The investigator hypothesizes that anesthetizing the urethral with
      lidocaine gel will decrease voiding efficiency as measured by standard bladder testing
      (urodynamic testing).
    

Detailed description: 
      1. Purpose of the Study

           The purpose of this study is to determine whether urethral sensory feedback has a role
           in the micturition (bladder emptying) reflex in female controls during routine office
           Urodynamic Studies (UDS). UDS are current clinical tests of urethral and bladder
           function and consist of several individual studies including filling cystometry,
           pressure-flow studies, and urethral pressure profilometry (UPP). Filling cystometry
           focuses primarily on sensation and activity of the bladder during the filling (or
           storage) phase of the micturition (voiding) cycle. Pressure-flow studies (which include
           voiding cystometry) are used to assess the motor activity of the bladder muscle during
           bladder emptying. UPP assesses urethral sphincter motor function and has traditionally
           been used to evaluate stress urinary incontinence. Perineal patch electromyography (EMG)
           is often added to UDS to assess for pelvic floor muscle recruitment during voiding,
           which may suggest voiding dysfunction.

        2. Background & 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 (Fowler,
           Griffiths et al. 2008). During the micturition (bladder emptying) reflex, the
           elimination of urine is facilitated by bladder wall contraction and urethral wall and
           pelvic floor muscle relaxation. Urine that subsequently flows through the urethra also
           activates sensory nerves to amplify bladder contractions and maintain efficient bladder
           emptying (Jung, Fraser et al. 1999, Bump 2000). Incomplete voiding and urinary retention
           occurs when these mechanisms are disrupted or poorly coordinated.

           Incomplete bladder emptying due to detrusor underactivity is an understudied health
           concern for women in the United States. The overall incidence of detrusor underactivity
           in women has not yet been reported in the literature. One study by Wu et al. (2005)
           determined that 7.8% of patients in an outpatient rehabilitation facility had symptoms
           of incomplete bladder emptying; whereas, 21% of people without symptoms had elevated
           post void residuals when universally screened. Their population consisted of 350
           patients, of which two-thirds were women. Lower urinary tract symptoms, including
           urinary urgency, frequency and incomplete bladder emptying, have been shown to decrease
           quality of life, increase healthcare utilization, decrease workplace productivity, and
           impact intimate relationships (Richter et al. 2007, Coyne et al. 2003).

           The current clinical management options for women with retention are intermittent or
           indwelling catheterization, urethral dilation, or reconstructive surgery (Mevcha and
           Drake 2010). These treatments, however, often fail to completely resolve lower urinary
           tract symptoms and the patients may develop chronic retention complications such as
           overflow incontinence, hydroureter, hydronephrosis, infection, or renal failure. In
           order to improve therapeutic outcomes, there is still a need to clarify the specific
           mechanisms that underlie detrusor underactivity in women. Our proposed studies will be
           contributing to the growing body of literature implicating urethral sensory feedback as
           a candidate to recover efficient bladder emptying.

        3. Hypothesis and Justification

           Overall Hypothesis: Urethral afferent nerve fiber activation augments bladder
           contractions for efficient voiding and urethral anesthesia will disrupt sensory feedback
           and impair bladder emptying.

           Specific Aim 1: To assess voiding efficiency (voided volume/{voided volume + residual
           volume}) in women controls with and without urethral anesthesia.

           Hypothesis 1a: Voiding efficiency will be lower when the urethra is anesthetized during
           uroflow studies

           Hypothesis 1b: Detrusor contraction at maximum flow rate (Pdet@Qmax) and duration of
           detrusor contraction will be reduced when the urethra is anesthetized during micturition
           pressure-flow studies

           Hypothesis 1c: Voiding while anesthetized will lead to increased valsalva-voiding
           (increased intra-abdominal pressure, Pabd) and an intermittent urinary stream during
           micturition pressure-flow studies

           Specific Aim 2: To assess whether urethral anesthesia gel improves discomfort during the
           UDS

           Hypothesis 2a: Visual Analog Scale (VAS) scores for pain will be lower during the UDS
           when the urethra has been anesthetized

        4. Studies Supporting Specific Aims:

           i. Micturition with Urethral Anesthesia: Distension and fluid flow in the urethra has
           been previously demonstrated to evoke sensory nerve discharge. Nerve firing originating
           from the urethra is then able to initiate contractions in the filling bladder and
           increase the amplitude and duration of ongoing bladder contractions. This
           pudendal-bladder reflex has been shown to be necessary for efficient bladder emptying
           because disruption to urethral sensory feedback by transection of the sensory branch of
           the pudendal nerve or intraurethral anesthesia reduces voiding efficiency in the rat.
           Urethral anesthesia in humans has also been demonstrated to increase post void residual
           and alter symptoms experienced during the voiding phase.

           This investigator's approach is novel as this study will characterize voiding in healthy
           women who will be randomized to placebo versus urethral anesthesia. Investigators will
           do this by performing UDS, which will include all clinical tests for bladder function,
           with or without urethral anesthesia (4% lidocaine hydrochloride gel or plain aqueous
           gel).

           ii. Pain Perception During Catheterization: Urethral catheterization elicits mild to
           moderate pain in women. The use of lubricant anesthetic on the catheter is one available
           option to manage tissue trauma and pain perception. Several studies have reported that
           4% lidocaine gel reduces procedural pain during female urethral catheterization. Others
           however, have found that lubricant anesthetic and catheter size, does not effect the
           perception of pain in urethral catheterization in women. These discrepant reports
           suggest a consensus has not been reached on the efficacy of lubricant anesthetic and
           pain perception in women.

        5. Subject Recruitment: Subjects will be recruited from Duke Hospital and Duke University
           Campus via newspaper advertisements and paper fliers.

        6. Design and Procedures: To account for screen failures, it is anticipated that a total of
           30 female controls will be screened to achieve n=20 for completed UDS. Participants will
           be randomized to their arm of the study using a random number generator. Study staff and
           the subjects will be blinded to the treatment regimen; thus, our study design is a
           randomized double-blind placebo-controlled trial.

      Study Visit Questionnaires and Tests: After their phone screen, participants will be
      scheduled for the study visit. All study procedures will take place at the Duke Urogynecology
      Office at Patterson Place. Participants will undergo informed consent on arrival to their
      study visit. They will provide a urine specimen for a point of care urinalysis and pregnancy
      test. Pre-procedure vital signs, including height and weight will be obtained. They will fill
      out the following questionnaires: Lower Urinary Tract Symptoms Tool, Sociodemographics and
      Functional Comorbidity Index and complete a Medication List.

      If subjects have a negative urinalysis and pregnancy test they will undergo examination to
      ensure no evidence of pelvic organ prolapse. A baseline uroflow study will then be performed.
      The subject will be instructed to void on a commode chair. A post void residual urine
      measurement will be performed via a bladder scanner. The subject will then complete a
      baseline VAS. Provided the subject has a normal baseline uroflow and no reported pain on
      baseline VAS, the subject will be randomized to an arm (lidocaine or aqueous gel first) of
      the urodynamic study. If either of their point of care tests is positive (per exclusion
      criteria), they will be excluded from the study and referred to their primary care physician.

      Prior to performing UDS, the subject's bladder will be scanned transabdominally with a
      standard clinic bladder scanner. This will ensure adequate urine is within the bladder prior
      to beginning. If the subject has > 250mL and < 650mL in their bladder, they will proceed to
      the UDS procedure room. If the subject has < 250 mL, they will be given a bottle of water and
      will return to the waiting room for 15-30 minutes. Adequate urine volume will again be
      confirmed via bladder scanning. Urodynamic testing will then begin.

      Order of Studies Performed During Urodynamic Testing: Complex Uroflowmetry, Complex
      Cystometry, Urethral Pressure Profilometry, Micturition Pressure-flow Study

      The Visual Analog Scale (VAS) will be administered to assess discomfort at the following
      times; after uroflow but before PVR (for baseline and the second study condition uroflow),
      immediately after the urethral catheter is placed, after 100mL of fluid has been instilled,
      and at full bladder capacity (MCC).

      After the completion of both UDS procedures, participants will be given standard
      Urogynecology post urodynamics instructions.
    

Intervention name(s): lidocaine gel; Plain aqueous gel
Intervention type(s): Drug; Other
Intervention description(s): Lidocaine (4%) gel from Quest Products, Inc.; KY jelly lubricant from Reckitt Benckiser
Other intervention name(s): 4% lidocaine; KY gel
Intervention MeSH terms: Lidocaine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: voiding efficiency; detrusor underactivity; urodynamics