Pharmacological Management of Non-Neuropathic Overactive Bladder
Flowcharts & Appendices
Algorithm: Stage 1
Algorithm: Stage 2
Algorithm: Stage 3
Appendix B: Assessment of Childhood Daytime Urinary Incontinence Red Flag Signs
Appendix C: Recommended Daily Fluid Intake
Appendix D: Bladder Diary
Appendix E: Bowel Chart
Appendix F: Referral Form
Appendix G: Medicines for Children Information Form
(from https://www.medicinesforchildren.org.uk/medicines/oxybutynin-for-daytime-urinary-symptoms)
Introduction, Scope & Purpose
The aim of this document is to offer the health care professional specific guidance on pharmacological management of overactive bladder (OAB) diagnosed as the cause for daytime urinary incontinence (DUI) following assessment. 

Most children will have attained daytime bladder control by the age of 4 years, but many children have occasional wet episodes during the day beyond this age. Investigation and management of daytime wetting is only indicated after the age of 5 years, up to this point incontinence lies within the range of normal development.
According to The International Children’s Continence Society (ICCS) a diagnosis of DUI is applied when a child over 5 years of age has:-
  • Involuntary, intermittent leakage of urine during the day
  • That occurs more than once per month for ≥ 3 months.

DUI in school aged children is distressing, having a damaging impact on quality of life and a negative influence on social, emotional, and behavioural well-being.

DUI requires timely assessment and management. Quality of Life improvement is the foundation of treatment.

To establish the cause of DUI a comprehensive general and bladder specific assessment of the child is needed to facilitate correct recognition of the condition causing the wetting.

For guidance on how to assess the patient presenting with DUI see the PIER guideline Assessment of childhood daytime urinary incontinence.

The goal of evaluation is to:
  • Recognise signs that indicate possible underlying neurological or anatomical causes (Red flag signs see appendix B) that require onward referral to specialised services
  • Facilitate diagnosis of the correct functional cause of DUI
  • Prevent over investigation and examination 
  • Guide an appropriate stepwise management plan.
 
The functional causes of DUI in children include:

  • Over active bladder (OAB)
  • Voiding postponement
  • Underactive bladder
  • Dysfunctional voiding
  • Stress urinary incontinence
  • Vaginal reflux
  • Giggle incontinence.

Although the pathophysiology’s of these conditions differ, a stepwise approach is essential to treat all functional causes of DUI, starting with behaviour modification, medical management and finally more invasive procedures.
 
OAB and Giggle incontinence are the only functional causes of DUI that should be treated with anticholinergics. This guideline has been developed based on national and international current best practice and expert opinion. It is summarised in the accompanying flow chart on the PIER website.

This guideline has been developed to guide all staff involved in the management of children over 5 years of age with non-neuropathic daytime urinary incontinence due to OAB.

It aims to provide best practice guidelines to ensure that, whenever a child with non-neuropathic daytime urinary incontinence due to OAB is treated, common standards are maintained.
Definitions​
The following definitions are taken from the International Childrens Continence Society document, The standardization of terminology of lower urinary tract function in children and adolescents. (https://doi.org/10.1016/S0022-5347(06)00305-3)

  • Continuous incontinence – continuous leakage of urine, not in discrete portions.
  • Dysfunctional voiding - habitual contraction of the urethral sphincter and/or pelvic floor musculature during voiding, resulting in an interrupted urinary flow and prolonged voiding time.
  • Dysuria - burning or discomfort during micturition.
  • Expected bladder capacity – age related expected maximum voided volume.
  • Giggle incontinence - involuntary complete bladder emptying during laughing with otherwise normal bladder and bowel function. It is not the same as dampness on laughing, which can be a manifestation of OAB.
  • Hesitancy - difficulty in initiating voiding when the child is ready to void.
  • Holding manoeuvres – strategies used to postpone voiding or supress urgency that maybe associated with bladder over activity.
  • Intermittent incontinence – intermittent leakage of urine in discrete portions.
  • Incomplete bladder emptying – post void residual volume in excess of 5 -20mls immediately after voiding.
  • Increased daytime urinary frequency - ≥ 8 voids per day.
  • Maximum voided volume – the largest voided volume.
  • Nocturia - the child is woken at night by the desire to void.
  • Nocturnal Enuresis – intermittent incontinence of urine while sleeping.
  • Nocturnal polyuria – nocturnal urine output exceeding 130% of expected bladder capacity.
  • Overactive Bladder (OAB) - Urinary urgency, usually accompanied by frequency and nocturia, with or without urinary incontinence, in the absence of urinary tract infection or other obvious pathology.
  • Post micturition dribble – the occurrence of involuntary leakage of urine immediately after voiding has finished.
  • Post void residual – urine left in the bladder immediately after voiding.
  • Straining – the need to make an intense effort to increase intra-abdominal pressure in order to initiate and maintain voiding.
  • Stress incontinence – the involuntary leakage of small amounts of urine with effort or physical exertion that increases intra-abdominal pressure such as coughing or sneezing. Also associated with obesity.
  • Underactive bladder - the child needs to strain to raise intra-abdominal pressure to initiate, maintain or complete voiding. Associated with low voiding frequency overflow incontinence, a large post-void residual is common.
  • Urinary urgency - a sudden, unexpected immediate and compelling desire to void.
  • Urethral-vaginal reflux – the urinary stream is directed towards the vagina. Caused by poor toilet posture and compression of the thighs or entrapment of urine by a fused labia.
  • Voiding frequency – the number of voids per day.
  • Voiding postponement - the child habitually delays voiding as long as possible and consequently wets due to an uninhibited bladder contraction due to an over filled bladder. Children often present with low voiding frequency, < 4 voids per day.
  • Weak stream – an observed steam or uroflow that is weak
Overactive Bladder
OAB is the most common functional cause of DUI and the estimated prevalence is about 15% in school aged children. Prevalence is known to decrease with age. It is a disorder of the storage (filling) phase of the bladder cycle.
Clinical Signs
Around 70% of children with OAB will present with urinary urgency as the predominant symptom. Other symptoms are:
  • Increased voiding frequency of >8 voids per day
  • Decreased voided volumes less than 50% of expected bladder capacity
  • Urge incontinence ranging from small damp patches to involuntary complete bladder emptying
  • Nocturia
  • Nocturnal enuresis.

Most parents will report that their child waits too long to go to the toilet. However, instead the bladder generally contracts too early. Parents must be informed that overactive bladder contractions can occur at any stage of bladder filling and that the urge disappears when the contractions stop.

Children with OAB often adopt behaviour patterns or holding manoeuvres to postpone wetting caused by uninhibited detrusor contractions. These include:
  • Standing on tip toes
  • Forceful leg crossing
  • Pinching the glans penis (boys)
  • Pressing on perineum (girls)
  • Squatting with the heel pressed to the perineum (Vincent’s Curtsey ) (girls).

Up to 50% of children with DUI will have co morbid constipation which should be addressed before treating daytime DUI. For some children DUI is entirely caused by constipation.

Constipation management needs to continue throughout all DUI treatment plans.

Guidance can be found at www.nice.org.uk/guidance/CG99. (Constipation in children and young people: diagnosis and management).
Initial Standard Management
Behavioural modification is the standard initial management and should include:

Educating children/parents about:
  • The co-existence of bladder and bowel problems so that there is understanding of why the bowels are such a focus for the child with OAB
  • Lower urinary tract anatomy and function
  • Demystification of pathophysiology
  • Therapeutic approaches so realistic treatment goals are set.

Focused micturition behaviour: 
  • Timed voiding
  • Avoidance of holding manoeuvres
  • Teaching of optimal voiding body positions
  • Use of a bladder diary as a reference source and documentation of progress.

Fluid intake/diet:
  • Adequate fluid intake for age as per NICE guidance (Appendix C)
  • Suggest a drink with each meal and snack, spread over the day
  • Avoidance of caffeinated, carbonated, hot chocolate drinks, citrus juices, squashes (especially blackcurrant) and artificial sweeteners which can be bladder irritants
  • Follow routine nutritional guidelines to avoid constipation and obesity
  • Use of a stool diary as the reference source and documentation of progress of constipation management/avoidance.

Re-education:
  • Address any adherence issues and re-educate if required.

Active behavioural modification should be continued until the child is dry. If no improvement is seen then pharmacological treatment can be added. 
Frequency Volume Chart
A chart should be completed immediately before pharmacological treatment is commenced to provide:
 
  • Objective evidence of continuing OAB
  • Baseline assessment of symptoms and bladder capacity
  • Assurance that fluid intake is adequate and spread throughout the day
  • Assurance that no bladder irritants are being consumed
  • Assurance that the child is voiding at least 4 times per day.
 
The chart should be completed over 2 days, not necessarily consecutive.
 
An example can be found in Appendix D and downloaded.
 
It is important that the child/carers understand the need to record the following:
  • Episodes of urgency and urge incontinence
  • Size of incontinence episode, (damp patch, wet pants, total change of clothes)
  • Fluid intake to include time, type and volume taken
  • Every void day and night to include time of void and voided volume.

Important information can be extrapolated from these charts, including:
  • Voiding frequency
  • Total voided volume in 24 hours
  • Average voided volume
  • Largest and smallest voided volume (functional bladder capacity)
  • Distribution of urine volume through the day and night
  • Urine loss and fluid intake.
 
At the age of 5 years a child should have an expected bladder capacity of around 180mls and void between 4 -7 times per day, at intervals of no less than two hourly.
 
Children who void ≥ 8 times per day have daytime urinary frequency.
 
Children who void ≤ 3 times per day have decreased daytime urinary frequency. Normal bladder capacity can be estimated in the child over the age of two and prior to adolescence, by using the formula (age + 1) x 30 = capacity in mls.
Bowel/Stool Diary
Constipation is common in children with DUI and should be assessed and managed to optimise treatment results.
 
The stool diary should be completed over at least 7 consecutive days as a minimum.
 
An example based on the Bristol stool chart can be found in Appendix E and downloaded.
 
Where constipation has previously been a problem consider close monitoring of bowels during anticholinergic treatment as constipation maybe exacerbated.
 
If this is not possible a new diary should be completed prior to a change in medications ie when moving to a different anticholinergic.
 
It is important that the child/carers understand the need to record the following:
  • Every stool passed day and night to include time
  • Type of stool as per Bristol stool chart
  • Amount of stool
  • Any episodes of soiling.

The signs and symptoms of childhood idiopathic constipation include:
  • Infrequent bowel activity, less than 3 per week
  • Painful defecation
  • Foul smelling wind and stools
  • Excessive flatulence
  • Irregular stool texture
  • Passing occasional enormous stools or frequent small pellets
  • Withholding or straining to stop passage of stools
  • Soiling or overflow
  • Abdominal pain
  • Distension or discomfort
  • Poor appetite
  • Lack of energy, an unhappy, angry or irritable mood
  • General malaise.​
Bladder Ultrasound Scan
If considering a screening USS it should be performed initially with the bladder full before voiding and include a post void image.
 
  • Evaluation of the bladder after voiding can demonstrate residual urine. To be reliable, the post-void scan should be performed immediately and is only valid if recorded within 5 minutes of voiding
  • A residual amount of more than 10% of expected bladder capacity for age (in ml) is considered significant
  • Upper tract dilatation can signify increased bladder storage pressures
Pharmacological Treatments
Pharmacological management is second line treatment and is introduced if the above interventions are not sufficient to achieve continence.
 
Behaviour modification should continue alongside pharmacological treatment and be reassessed at every stage.
 
Anticholinergic medications influence the reservoir function of the bladder through their inhibitory effect on the detrusor muscle. They increase bladder capacity and compliance and reduce detrusor over activity.

In the child that develops a urinary tract infection whilst on anticholinergic treatment a post void residual scan should be obtained and anticholinergics may need to be stopped.
Oxybutynin
  • Currently the only anticholinergic approved for the treatment of overactive bladder symptoms in children older than 5 years, therefore the first line agent of choice.
  • Several studies have shown a significant improvement of symptoms with oxybutynin but it has a high side effect profile including dry mouth, dry eyes, dry skin, constipation, abnormal vision, facial flushing, sleep difficulties and sporadic changes in behaviour. Oxybutynin crosses the blood brain barrier
  • Oxybutynin is an unselective anticholinergic drug that has a direct antispasmodic effect by inhibiting muscarinic actions of acetylcholine on smooth muscle. It relaxes the detrusor (bladder) muscle, thereby increasing bladder capacity, decreases the frequency of uninhibited detrusor muscle contractions and delays initial desire to void
  • Oxybutynin is short acting; it has a 3 – 4 hourly half-life. This can be extended if taken with food
  • Dosage can be titrated to the time of maximal complaints
  • Comes in two forms, immediate (IR) and modified release (MR).
 
​Dose
 
Immediate Release
  • Child age 5-11years: 2.5-3mg twice daily initially, increase to 5mg, 2-3 times per day.
  • Child age 12-17 years: 5mg, 2-3 times per day.
 
IR in tablet form can be crushed and hidden in a small quantity of cold food e.g. a teaspoon. Some tablets will disperse in water. Contact pharmacy for advice. IR is also available as a liquid preparation, however this is expensive and not always easily available.
  • Tablets come in 2.5mg, 3mg and 5mg
  • Oral solution comes in two strengths 2.5mg in 5ml, or 5mg in 5ml
  • Sugar free oral solution is available.
 
In children over 5 years, the modified release form of oxybutynin can be used if compliance problems are seen with immediate release preparations, and the child is able to swallow tablets whole (not suitable for crushing).  Initially 5mg once daily adjusted according to response in steps of 5mg at weekly intervals, to a maximum dose of 15mg once daily of the MR preparation.
 
Dose equivalence and conversion to modified release
Children 5 years and over taking immediate-release oxybutynin may be transferred to the nearest equivalent daily dose of modified release preparation  to a maximum of 15mg once daily.MR comes as 5mg or 10mg:
  • Must not be crushed
  • Better tolerability and efficacy compared to IR.
 
In patients with side effects or with unsatisfactory response, next line of oral medication is tolterodine or solifenacin.
 
Response definitions
According to International Children’s Continence society criteria:
  • ·Complete response is taken to be 100% improvement of symptoms
  • Response is taken to be 90 to 99% improvement of symptoms
  • Partial response is taken to be 50 to 89% improvement of symptoms
  • No response is taken to be <50% improvement in symptoms
Tolterodine
  • Tolterodine is not currently licensed for use in children but has been extensively studied and is routinely used as an alternative to oxybutynin if side effects prevent continuation
  • Tolterodine acts on M2 and M3 subtypes of muscarinic receptors so is more uro -selective and does not cross the blood brain barrier 
  • Side effect profile includes dry mouth, dry eyes, dry skin, constipation, abnormal vision, facial flushing, sleep difficulties and sporadic changes in behaviour
  • Comes in two forms, immediate (IR) and modified release (MR).
  • Effects are usually seen within 4 weeks.
  • Avoid use with macrolides, imidazoles and triazole antifungals and protease inhibitors as they may result in increased tolterodine concentrations.

Dose
 
By mouth, using immediate release tablets.
  • Child age 2-17years: 1mg once daily initially, increase to 2mg, 1 to 2 times per day according to response.
 
IR in tablet form can be crushed and hidden in a small quantity of cold food e.g. a teaspoon. Tablets are available as 1mg and 2mg. 

By mouth using modified release capsules.
  • Child age 2-17 years: 2mg initially which can be increased to 4mg once daily.
 
MR comes as 2mg or 4mg:
  • Must not be crushed
  • Lower side effect profile compared to IR.
 
Dose equivalence and conversion
Children stabilised on immediate-release tolterodine 2 mg twice daily may be transferred to modified release tolterodine 4 mg once daily if compliance problems are seen .
Solifenacin
  • Solifenacin is not currently approved for use in children with over active bladder. (licensed from the age of 2 years for children with neuropathic over active bladder) but it has been extensively studied and is routinely used as an alternative to oxybutynin if side effects prevent continuation.   
  • Solifenacin is a selective anticholinergic with high affinity for M3 receptors
  • Studies have shown that solifenacin decreases episodes of incontinence and frequency and is tolerated in children previously resistant to oxybutynin or tolterodine.
  • Solifenacin is prescribed as a once daily dose but is not a modified release tablet so can be crushed.
 
Dose
 
By mouth, over 4 years
  • Initially 5mg once a day.
 
Tablets can be crushed and hidden in a small quantity of cold food or water e.g. a teaspoon, although the taste is very bitter.
 
If required the dose can be increased to 10mg once a day
 
Comes as 5mg and 10mg tablets:
Mirabegron
Mirabegron can be considered in children over 8 years old (off-label). It should only be used if anticholinergics are ineffective, contraindicated or not tolerated. Combination treatment with anticholinergics and mirabegron are an option for patients who fail to respond to monotherapy.
  • In adults mirabegron has been shown to be effective for the treatment of OAB, with few side effects. It is an off- label option for children.
  • Mirabegron is a selective beta-3 adrenoceptor agonist with a different pharmacologic profile and mechanism of action to anticholinergics
  • Bladder relaxation is obtained through activation of the beta-3 adrenoceptor.
  • One study reported a complete response rate in 22% of 58 children, and almost all the patients experienced some improvement in the severity of the symptoms of incontinence.
 
If anticholinergics drugs are contraindicated, or have unacceptable side effects, mirabegron can be used in isolation having reassessed bowel management, fluid intake and voiding habits.
 
Dose
 
Child over 8 years
  • Initially 25mg once a day. Increase to maximum of 50mg if necessary.
 
Tablets are modified-release. They must be swallowed whole and must not be chewed, divided or crushed.
 
Mirabegron can increase blood pressure. Use with extreme caution in patients with pre-existing hypertension.
 
Blood pressure should be recorded at the start of treatment and at every clinic review.
 
Although the local formulary allows for initiation of mirabegron in primary care, i t is anticipated that mirabegron  in children will be initiated by secondary care services. Where demonstrated that it has been effective and tolerated, prescribing may be continued by primary care with agreement of the patient’s GP. Ensure clear explanation and communication of dosing, monitoring, etc as mirabegron is not listed in the BNFc
Management of Giggle Incontinence
True giggle incontinence is a complete or almost complete emptying of the bladder caused by an involuntary detrusor contraction in response to laughter, with no other lower urinary tract dysfunction.
 
It is more common in girls than boys, and most prevalent in the pre-pubertal years. 
 
A child with Giggle Incontinence will be over five years old, and will usually have;
  • No history of constipation or UTI
  • Normal volume voids ([age+1] x 30)
  • Normal frequency voids (4 – 7 /day)
  • Little or no urgency
  • Large volume wetting solely associated with laughter
  • No incontinence with coughing or physical activities

Behaviour modification is the standard initial management as discussed for OAB.
 
Persistence of giggle incontinence interfering with daily activities is an indication to commence medication. First line medication is an anticholinergic.
 
Doses are the same as in OAB management. Oxybutynin should be used first line. Tolterodine or solifenacin can be used in children whose symptoms are resistant to oxybutynin.
 
 If no response to anticholinergics then  methylphenidate can be considered, but under specialist use.
Referral to Level 3
It is expected that patients will have completed stage two /three of the prescribing algorithm before being referred to level 3 urology services for persistent DUI resistant to pharmacological treatment.
 
Referral can be made using the form in Appendix F.  This should be completed and sent with a referral letter to the Paediatric Urologists.
 
Please note that referral should not be made if:
  • Child is under 5 years old.
  • Has not been seen in a Level 2 service and treated to stage 3 on the algorithm.
  • Constipation has not been ruled out or affectively treated (evidenced by a stool diary)
  • The FVC shows less than 4 voids per day.
  • The FVC shows fluid intake below that expected for age (see Appendix B).
  • Bladder irritants are being consumed.
 
Please ensure all sections of the form are complete