Case Control Study to Investigate the Use of Urethral Pressure Profile Measurement in Children
Case Control Study to Investigate the Use of Urethral Pressure Profile Measurement in Children
The bladder has a muscle that acts like a tap called the sphincter. Just like a tap, when pee
 is stored the sphincter muscle is closed and during peeing the sphincter opens. Sometimes the
 sphincter tap does not work properly and can cause problems. If the sphincter is weak there
 can be urine leak (incontinence). If the sphincter is too strong bladder might not empty
 properly.

 Children who require investigation of their urinary problems are usually assessed with
 non-invasive tests. Sometimes investigation is with a more invasive test videourodynamics or
 video cystometrogram (VCMG; this test requires the insertion of catheters into the bladder
 and rectum. This test provides only indirect information about sphincter function.

 It would be helpful to have a more direct test of the sphincter. It will allow better
 targeted treatments of sphincter problems which are often therapeutically challenging.
 Urethral pressure profile is a test used in adults to assess the sphincter. Although it has
 been described in children normal values have not been described.

 The research project is to define urethral pressure profile values in children and young
 people with normal, weak and overactive sphincters.

 Urethral pressure profile measurement is invasive as it requires the insertion of a special
 catheter. It will therefore be performed at the time of other invasive procedures eg VCMG or
 urology surgery under general anaesthetic.

 The study will be conducted at single site, which is a children's hospital. The study will be
 an observational case controlled study with three arms: controls, those with overactive
 sphincters and those with underactive sphincters. The study is intended to run over three
 years.
Rationale Bladder problems in children are common resulting in incontinence and social
 distress.

 The bladder performs two functions: storage and emptying. It has two components that act
 synchronously with each other and allow it to achieve this: the detrusor and the sphincter
 complex. The detrusor is the muscle in the wall of the bladder. The sphincter complex is a
 group of muscles that act on the urethra, which is the outlet of the bladder. During storage
 the detrusor muscle is relaxed while the sphincter complex is closed. During bladder emptying
 the detrusor muscle contracts while the sphincter relaxes. Abnormal function of either
 component will result in abnormal bladder function including lower urinary tract symptoms
 (including frequency urgency, incontinence, difficulty voiding) and danger to the kidneys.
 Specifically, abnormality of the sphincter will result in either incontinence during storage,
 or obstructive problems during voiding.

 Establishing a bladder diagnosis in children is helped by performing a test of bladder
 function. In the majority of children this can be done with non-invasive assessments that
 include bladder diary, flow rates, flow patterns residual volume measurements and
 electromyogram (EMG) using skin electrodes. However, in some children non-invasive testing is
 not able to provide enough information and so videocystometry (VCMG), or urodynamics, are
 performed. These are more invasive tests. Catheters are inserted into the bladder and abdomen
 (usually the rectum) to measure pressures generated by the detrusor. The flow rate is
 measured during emptying. Combining this with x-ray fluoroscopy provides additional
 anatomical information. VCMG provides direct information about the detrusor. Standard VCMG in
 children do not currently provide direct information about the tone of the sphincter.
 Information about sphincter function is provided indirectly by measuring the pressures during
 leaking, or during voiding from analysis of flow, pressure and X-ray imaging.

 The investigators believe that there is a need to develop a direct diagnostic test of
 sphincter function in children. The investigators have a practice where children are seen
 with both sphincter underactivity and overactivity. Sphincter under- activity is most
 commonly seen in children with abnormal bladder function as a result of neurological disease
 (neuropathic bladder). Sphincter incompetence can be difficult to treat in children . A
 diagnostic test that can better define the condition may allow better targeted treatments.
 Sphincter overactivity will result in a poorly emptying bladder. However poor bladder
 emptying can also result from detrusor underactivity. In patients with incomplete bladder
 emptying it can be difficult to distinguish whether the condition is as a result of
 underactive detrusor or overactive sphincter (e.g. dysfunctional voiding or high-tone
 non-relaxing sphincter type conditions). The distinction is important because the two
 conditions require very different treatments.

 There are tests of sphincter function:

 -  Abdominal leak point pressure (ALPP). This is performed during VCMG. It is the lowest
 pressure measured in the bladder at which leaking happens during a series of
 increasingly more forceful Valsalva manoeuvres or cough. It is dependent on incontinence
 occurring. It is an indirect test of sphincter function; the pressure in the bladder at
 the precise moment of leaking provides the measure of sphincter tone. It can sometimes
 be difficult to get children to perform this test.

 -  Retrograde leak point pressure (RLPP). This is a test of sphincter weakness performed in
 men. A catheter is inserted into the male urethra and x-ray contrast is injected. The
 RLPP is the lowest pressure required for the contrast to overcome the sphincter and
 enter the bladder. The test requires an adequate length of urethra and so can only
 practically be used in males.

 -  Electromyogram (EMG). Electrodes can be used to measure electrical activity. In children
 skin electrodes are used; this makes it difficult to distinguish between pelvic floor
 and sphincter activity. Invasive needle electrodes can be used to specifically target
 the sphincter, but this is cumbersome, invasive and offered in very few units. EMG
 provides qualitative information on whether there is overactivity of muscles being
 recorded.

 -  Videocytometogram (VCMG). Described above, this can give an assessment of the presence
 of overactive sphincter during voiding based on an evaluation and opinion from pressure
 flow and x-ray appearance during voiding.

 -  Urethral pressure profile (UPP). Pressure recording catheters are passed through the
 sphincter to directly measure the pressure applied by the sphincter. This technique can
 be used to identify both overactive and underactive sphincter activity. The technique of
 UPP is used to derive the maximum urethral closure pressure (MUCP). This is the maximum
 difference between the urethral pressure and the intravesical pressure .

 Urethral pressure profile measurement carries great promise as a diagnostic test. It has been
 validated in adults to diagnose sphincter weakness as well as diagnosing high tone
 non-relaxing sphincter disorders. The test is easy to perform. Its use has previously been
 described in children; in this early description it was found not to be helpful in diagnosing
 bladder outlet obstruction. However, one of the conditions for which UPP shows promise is
 high tone non-relaxing sphincter, which was not described as a clinical entity until a later
 time. However UPP has not been validated in children.

 The investigators propose a study to investigate the use of UPP in children. The hypothesis
 is that there are values and characteristics of the UPP that can distinguish control patients
 from those with either sphincter underactivity and sphincter overactivity.

 The investigators will measure MUCP in three patient groups and compare the values. These
 three groups will be discussed in more detail:

 Controls. These patients will have no known bladder disease. This will be asked in
 pre-recruitment checks. The patients will complete a validated questionnaire- the
 Dysfunctional Voiding Scoring System (DVSS). A normal score, ie less than less than 6 in
 girls and less than 9 in boys, will indicate that the child has no significant urinary
 symptoms.

 Measurement of UPP is invasive, requiring a fine catheter to be passed through the urethra;
 performing it in an otherwise well child presents difficulties. UPP's will therefore be
 measured under general anaesthetic in children who require general anaesthesia for other
 urological conditions, eg renal stones. Such a child will have much larger instruments passed
 through the urethra as part of their urology surgery so that performing a urethral pressure
 profile should not significantly add to their discomfort or risk. General anaesthetic will be
 induced with an inhalational anaesthetic agent. A light level of general anaesthesia will
 then be maintained with the same inhalation agent. This will avoid administration of
 intravenous anaesthetic agents which may affect UPP values . A light inhalational general
 anaesthesia has not been shown to affect UPP measurements. After the UPP measurement has been
 performed, which is expected to take less than five minutes, general anaesthesia will then be
 changed to a level sufficient for the planned urological procedure.

 Overactive sphincter These patients have presented to the bladder service with problems
 because of abnormality of sphincter activity. These children will be expected to have high
 tone sphincters. They may have varieties of diagnoses which include high tone non-relaxing
 sphincter, Fowler's syndrome and dysfunctional voiding. They will commonly have voiding
 symptoms such as hesitancy, straining, poor stream or the sensation of incomplete emptying.
 There is, perhaps, surprisingly high incidence of storage symptoms such as frequency urgency
 and incontinence.

 Detailed Description: Rationale Bladder problems in children are common resulting in
 incontinence and social distress.

 The bladder performs two functions: storage and emptying. It has two components that act
 synchronously with each other and allow it to achieve this: the detrusor and the sphincter
 complex. The detrusor is the muscle in the wall of the bladder. The sphincter complex is a
 group of muscles that act on the urethra, which is the outlet of the bladder. During storage
 the detrusor muscle is relaxed while the sphincter complex is closed. During bladder emptying
 the detrusor muscle contracts while the sphincter relaxes. Abnormal function of either
 component will result in abnormal bladder function including lower urinary tract symptoms
 (including frequency urgency, incontinence, difficulty voiding) and danger to the kidneys.
 Specifically, abnormality of the sphincter will result in either incontinence during storage,
 or obstructive problems during voiding.

 Establishing a bladder diagnosis in children is helped by performing a test of bladder
 function. In the majority of children this can be done with non-invasive assessments that
 include bladder diary, flow rates, flow patterns residual volume measurements and
 electromyogram (EMG) using skin electrodes. However, in some children non-invasive testing is
 not able to provide enough information and so videocystometry (VCMG), or urodynamics, are
 performed. These are more invasive tests. Catheters are inserted into the bladder and abdomen
 (usually the rectum) to measure pressures generated by the detrusor. The flow rate is
 measured during emptying. Combining this with x-ray fluoroscopy provides additional
 anatomical information. VCMG provides direct information about the detrusor. Standard VCMG in
 children do not currently provide direct information about the tone of the sphincter.
 Information about sphincter function is provided indirectly by measuring the pressures during
 leaking, or during voiding from analysis of flow, pressure and X-ray imaging.

 The investigators believe that there is a need to develop a direct diagnostic test of
 sphincter function in children. The investigators have a practice where children are seen
 with both sphincter underactivity and overactivity. Sphincter under- activity is most
 commonly seen in children with abnormal bladder function as a result of neurological disease
 (neuropathic bladder). Sphincter incompetence can be difficult to treat in children . A
 diagnostic test that can better define the condition may allow better targeted treatments.
 Sphincter overactivity will result in a poorly emptying bladder. However poor bladder
 emptying can also result from detrusor underactivity. In patients with incomplete bladder
 emptying it can be difficult to distinguish whether the condition is as a result of
 underactive detrusor or overactive sphincter (e.g. dysfunctional voiding or high-tone
 non-relaxing sphincter type conditions). The distinction is important because the two
 conditions require very different treatments.

 There are tests of sphincter function:

 -  Abdominal leak point pressure (ALPP). This is performed during VCMG. It is the lowest
 pressure measured in the bladder at which leaking happens during a series of
 increasingly more forceful Valsalva manoeuvres or cough. It is dependent on incontinence
 occurring. It is an indirect test of sphincter function; the pressure in the bladder at
 the precise moment of leaking provides the measure of sphincter tone. It can sometimes
 be difficult to get children to perform this test.

 -  Retrograde leak point pressure (RLPP). This is a test of sphincter weakness performed in
 men. A catheter is inserted into the male urethra and x-ray contrast is injected. The
 RLPP is the lowest pressure required for the contrast to overcome the sphincter and
 enter the bladder. The test requires an adequate length of urethra and so can only
 practically be used in males.

 -  Electromyogram (EMG). Electrodes can be used to measure electrical activity. In children
 skin electrodes are used; this makes it difficult to distinguish between pelvic floor
 and sphincter activity. Invasive needle electrodes can be used to specifically target
 the sphincter, but this is cumbersome, invasive and offered in very few units. EMG
 provides qualitative information on whether there is overactivity of muscles being
 recorded.

 -  Videocytometogram (VCMG). Described above, this can give an assessment of the presence
 of overactive sphincter during voiding based on an evaluation and opinion from pressure
 flow and x-ray appearance during voiding.

 -  Urethral pressure profile (UPP). Pressure recording catheters are passed through the
 sphincter to directly measure the pressure applied by the sphincter. This technique can
 be used to identify both overactive and underactive sphincter activity. The technique of
 UPP is used to derive the maximum urethral closure pressure (MUCP). This is the maximum
 difference between the urethral pressure and the intravesical pressure .

 Urethral pressure profile measurement carries great promise as a diagnostic test. It has been
 validated in adults to diagnose sphincter weakness as well as diagnosing high tone
 non-relaxing sphincter disorders. The test is easy to perform. Its use has previously been
 described in children; in this early description it was found not to be helpful in diagnosing
 bladder outlet obstruction. However, one of the conditions for which UPP shows promise is
 high tone non-relaxing sphincter, which was not described as a clinical entity until a later
 time. However UPP has not been validated in children.

 The investigators propose a study to investigate the use of UPP in children. The hypothesis
 is that there are values and characteristics of the UPP that can distinguish control patients
 from those with either sphincter underactivity and sphincter overactivity.

 The investigators will measure MUCP in three patient groups and compare the values. These
 three groups will be discussed in more detail:

 Controls. These patients will have no known bladder disease. This will be asked in
 pre-recruitment checks. The patients will complete a validated questionnaire- the
 Dysfunctional Voiding Scoring System (DVSS). A normal score, ie less than less than 6 in
 girls and less than 9 in boys, will indicate that the child has no significant urinary
 symptoms.

 Measurement of UPP is invasive, requiring a fine catheter to be passed through the urethra;
 performing it in an otherwise well child presents difficulties. UPP's will therefore be
 measured under general anaesthetic in children who require general anaesthesia for other
 urological conditions, eg renal stones. Such a child will have much larger instruments passed
 through the urethra as part of their urology surgery so that performing a urethral pressure
 profile should not significantly add to their discomfort or risk. General anaesthetic will be
 induced with an inhalational anaesthetic agent. A light level of general anaesthesia will
 then be maintained with the same inhalation agent. This will avoid administration of
 intravenous anaesthetic agents which may affect UPP values . A light inhalational general
 anaesthesia has not been shown to affect UPP measurements. After the UPP measurement has been
 performed, which is expected to take less than five minutes, general anaesthesia will then be
 changed to a level sufficient for the planned urological procedure.

 Overactive sphincter These patients have presented to the bladder service with problems
 because of abnormality of sphincter activity. These children will be expected to have high
 tone sphincters. They may have varieties of diagnoses which include high tone non-relaxing
 sphincter, Fowler's syndrome and dysfunctional voiding. They will commonly have voiding
 symptoms such as hesitancy, straining, poor stream or the sensation of incomplete emptying.
 There is, perhaps, surprisingly high incidence of storage symptoms such as frequency urgency
 and incontinence.

 A diagnosis of dysfunctional voiding will have been made based on voiding pelvic EMGs based
 on representative at least two representative voids.

 The children to be recruited will require VCMG urodynamics as part of their clinical care.
 Patients who are recruited to this arm of the study will in addition have a urethral pressure
 profile measurement performed on the same day as their VCMG.

 VCMG requires the insertion of urethral and rectal catheters. This is an invasive procedure.
 In a small group of children this is straightforward; these children perform intermittent
 catheterisation regularly to empty their bladder and so are used to having a catheter passed.
 However, in the majority passing a urethral catheter can be distressing and so in the
 investiators' unit catheter insertion for urodynamics is done either under general
 anaesthesia, for those under seven years, or with inhalational sedation (Entonox) for those
 above the age of seven years.

 Subjects who participate in this arm of the study will undergo VCMG. The UPP measurement will
 be done immediately before the insertion of the bladder catheter. If sedation or anaesthesia
 is required for the catheter insertion this will have been administered, lignocaine gel will
 be applied to the urethra (standard for catheter insertion prior to VCMG), a UPP measurement
 taken, and then the catheters inserted for urodynamics.

 Underactive sphincter Underactive sphincter results in the symptom of stress incontinence. In
 children the most common cause of urethral sphincter weakness is neurological disease that
 causes neuropathic bladder. These neurological conditions include children with spina bifida
 (e.g. myelomeningocele or closed spinal dysraphism). In the investigators' unit children with
 neuropathic bladder are frequently managed with intermittent catheterisation to empty their
 bladders and antimuscarinic medication to reduce bladder storage pressures; they undergo
 annual surveillance of their bladder with videocystometry urodynamics. They are familiar with
 catheters and VCMG.

 Stress incontinence is an unusual symptom in children. In the investigators' unit these
 children are frequently investigated with VCMG.

 Subjects recruited to this arm will either have symptoms of stress incontinence or have a
 neuropathic bladder associated with symptoms of urinary incontinence.

 Subjects who participate in this arm of the study will undergo VCMG. The UPP measurement will
 be done immediately before the insertion of the bladder catheter. If sedation or anaesthesia
 is required for the catheter insertion this will have been administered, lignocaine gel will
 be applied to the urethra (standard for catheter insertion prior to VCMG), a UPP measurement
 taken, and then the catheters inserted for urodynamics.

 The UPP's of these patients will be included for analysis if their subsequent urodynamics
 demonstrate either stress incontinence or continuous incontinence in the absence of
 simultaneous detrusor overactivity

 Hypothesis:

 Values and characteristics of MUCP during UPP measurement will be compared between the three
 groups to identify whether the groups can be distinguished based on these results. The
 hypothesis is that there are cut-off values for MUCP that can distinguish normal controls
 from those with overactive sphincter and also those with underactive sphincters.
Inclusion Criteria All subjects • Age 7-16 years inclusive

 Controls

 -  Concurrent urological disease requiring surgery which includes cystoscopy

 -  No significant urinary symptoms

 -  No day-time urinary incontinence

 -  Urinary frequency 4-7 per day

 -  No history of recurrent urinary infections (more than two infections in previous year)

 -  Has not passed a renal tract stone

 Overactive sphincter

 -  Require VCMG as part of their clinical care

 -  A prior diagnosis of dysfunctional voiding. This will have been made in a
 neurologically intact child following previous non-invasive bladder investigation
 including two representative urine flows that demonstrate the following (Austin et
 al., 2014):

 -  Intermittent and/or fluctuating flow rate

 -  Pelvic EMG activity during voiding

 -  either perform intermittent catheterisation or have no contraindication to Entonox
 sedation (see below)

 Underactive sphincter

 -  Have either:

 -  Symptoms of stress urinary incontinence

 -  Or urinary incontinence with a neuropathic bladder

 -  Require VCMG as part of their clinical care.

 -  either perform intermittent catheterisation or have no contraindication to Entonox
 sedation (see below)

 -  For the UPP data to be included for analysis their videocystometry should demonstrate
 o Stress urinary incontinence: defined as involuntary leakage of urine during
 increased abdominal pressure, in the absence of a detrusor contraction (Austin et al.,
 2014)

 Exclusion Criteria:

 -  Unaccompanied by adult with parental responsibility who can give consent

 -  Previous bladder outlet or urethral surgery

 -  Other urological disease not mentioned specifically in the treatment group inclusion
 criteria; including posterior urethral valves, cerebral palsy, inherited metabolic
 disease

 -  Contraindication to Entonox if sedation required for catheter insertion:

 -  Conditions where gas may be trapped in a body cavity, eg middle ear occlusion,
 intestinal obstruction

 -  Unable to understand instruction for use of Entonox

 -  Evidence urinary tract infection on day UPP measurement

 -  Symptoms of dysuria

 -  Abnormally cloudy or offensive urine

 -  Temperature of 38oc or more

 -  Urine dipstick positive nitrates or leucocytes on the day of the study, in the absence
 of a renal tract stone or indwelling catheter