BBUK Enuresis Update Spring 2020

Enuresis Update Spring 2020 5 Edition th

Bladder & Bowel UK’s Enuresis Award NEW Research Reviews Sharing Best Practice

Tel: 0161 607 8219 Email: bbuk@disabledliving.co.uk Web: www.bbuk.org.uk Bladder & Bowel UK, Disabled Living, Burrows House, 10 Priestley Road, Wardley Industrial Estate, 1 Worsley, Manchester, M28 2LY Registered Charity No: 224742

Improving treatment outcomes: considering the contributory factors to bedwetting Enuresis is now a recognized as a multifactorial or heterogeneous medical condition. It is classified as either monosymptomatic, where there are no daytime bladder symptoms; or non-monosymptomatic, when the child also presents with urgency, frequency or daytime wetting. Lack of arousability (not waking to bladder signals), nocturnal polyuria and factors affecting bladder capacity are all causes of bedwetting, with constipation, obstructive sleep apnoea, sub optimal fluid intake, dietary factors and screen use also being possible contributary factors.

As a result of the potential different factors causing enuresis in an individual child, single line treatments, such as desmopressin or alarm, have on average a success rate of around 60%. Therefore, about 40% of children will require combined treatment or other interventions, to address any contributory factors, in order to achieve dryness.

Staying dry at night is a fine balance between the volume of night-time urine produced and the ability of the bladder to store that urine until morning. For treatments to be effective all contributary causal factors will need to be resolved. For example, even if a treatment, such as desmopressin, is effective in reducing any nocturnal polyuria to a ‘normal’ night-time volume, unless the bladder has enough capacity the child will still wet.

This highlights the important of undertaking a holistic assessment prior to commencing any treatment, to ensure all underlying factors have been identified and addressed. This then facilitates the development of a structured individualized treatment plan based very much on the outcome of the assessment as well as the family dynamics and their preferred treatment choices.

An input and output chart, including recording the frequency and volume of urine passed, will help identify if there are any underlying bladder problems and with a careful history also identify if constipation is present (Hodges 2012). Studies have shown that the presence of constipation is often not recognized either by the child or the parent and importantly often the bedwetting has shown to be improved, if not resolved, once the constipation is treated (McGrath 2008). Any bowel or daytime bladder problems should therefore always be addressed first.

There is now a clear recognition of the association between sleep disorders and bedwetting. As a result, children who are reported to snore or have episodes of disrupted breathing during sleep should be referred for further assessment (Zaffanello 2017),as for some of these children bedwetting will resolve following successful treatment for this 2 condition.

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The child’s fluid intake needs to be optimized, water-based drinks encouraged, and carbonated and caffeinated drinks restricted. Diet has also been postulated as a contributary factor, with some debate regarding the role of dairy based products on urinary excretion (Ferrara 2015). There seems to be some emerging evidence regarding the effect of salty food on diuresis (Tsuji S et al 2020, Dehoorne 2006).

Although the evidence is not clear it might be beneficial to suggest that those foods that have high salt and dairy content are restricted in the evening.

Using self-luminous screens for more than two hours has been shown to affect children’s sleep and cause melatonin suppression (Chindamo 2007). Although there is currently no consensus regarding the direct impact this has on a child’s bedwetting (Ardura-Fernandez 2007) it would seem sensible to suggest that screens are not used in the hours before bedtime.

Addressing all the potential contributary factors first will give the child the best chance of achieving more formal treatment success.

References Ardura-Fernandez J et al (2007) Melatonin Rhythm in Children With Enuresis. BJU Int; 99(2):413-5 Chindamo S, Buja A, DeBattisti E et al (2019) Sleep and new media usage in toddlers. Eur J Pediatr. Apr; 178(4):483-490 Dehoorne JL, Raes AM, van Laecke E et al (2006) Desmopressin resistant nocturnal polyuria secondary to increased nocturnal osmotic excretion. J Urol. ; 176(2):749-53 Ferrara P, Del Volgo V, Romano V et al (2015) Combined Dietary Recommendations, Desmopressin, and Behavioral Interventions May Be Effective First-Line Treatment in Resolution of Enuresis. Urol J: 12(4):2228-32 Gradisar M, Wolfson A, Harvey A et al (2013), The Sleep and Technology Use of Americans: Findings From the National Sleep Foundation's 2011 Sleep in America Poll. J Clin Sleep Med; 9(12):1291-9 Hodges SJ, Anthony EY. (2012) Occult megarectum--a commonly unrecognized cause of enuresis. Urology. 2012 Feb; 79(2):421-4 McGrath KH, Caldwell PH, Jones MP et al (2008) The frequency of constipation in children with nocturnal enuresis: a comparison with parental reporting. J Paediatr Child Health. ;44(1-2):19-27 Tsuji S, Yamaguchi T, Akagawa Y, Akagawa S, Kino J, Yamanouchi S, Kimata T, Kaneko K (2020) High daily salt intake had a negative impact on how well nocturnal enuresis treatment worked on children aged 7-10 years. Acta Padiatrica 109, 193-197 Zaffanello M, Piacentini G, Lippi G et al Obstructive sleep-disordered breathing, enuresis and combined disorders in children: chance or related association? Swiss Med Wkly. 2017 Feb 3; 147:w14400.

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Cochrane Review Alarm Interventions for Nocturnal Enuresis in Children Caldwell PHY, Codarini M, Stewart F, Hahn D, Sureshkumar P The Cochrane Library consists of a collection of databases that contain evidence to support informed decisions in healthcare. The Cochrane systematic reviews are part of this collection. A systematic review aims to find, evaluate and synthesize all existing evidence to address a specific research question.

A review is approached by identifying relevant studies from a range of sources, evaluating the strengths or otherwise of the studies using predefined criteria, then collecting and appropriately synthesizing the data. The reviews may be updated as new evidence emerges.

The advantages of a Cochrane review are that they present findings clearly, indicate the quality of the evidence, as well as the size of the population included in studies. They may also include a meta-analysis. This is where individual study results are similar enough that they can be combined to produce a more accurate estimate of the outcome of an intervention.

On 4th May 2020 the Cochrane Incontinence Group published their latest review ‘Alarm Interventions for Nocturnal Enuresis in Children’. They included randomised or quasi-randomised trials of alarms alone, or alarms used with other treatments for bedwetting in children aged 5 - 16 years old. Seventy-four studies were included, with a total of 5983 children.

The authors state that: ‘The quality of the evidence means that, in general, the level of certainty in our conclusions is low.’ They conclude that alarms may be more effective than no treatment and that alarm in combination with desmopressin may be more effective than desmopressin on its own. However, they were unable to evaluate whether an alarm was more, or less effective than other treatments for bedwetting. They state that alarms do continue to have ‘an important place’ in the treatment of bedwetting.

The full Cochrane review is available online at: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD002911.pub3/full ?highlightAbstract=alarm%7Cenuresi%7Calarms%7Cenuresis

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Research Reviews Does smoking exposure affect response to treatment in children with primary monosymptomatic nocturnal enuresis?

Aksoy GK; Koyun NS, Dogan CS Journal of Pediatric Urology DOI 10.1016/j.jpurol.2019.10.012

Abstract The study investigated whether exposure to passive smoking due to parental use of cigarettes affected the response of children with primary monosymptomatic enuresis (PMNE) to Desmopressin.

The authors recognise that studies of adult women have demonstrated that smoking has negative impact on pelvic floor and detrusor muscle function and increases the risk of secondary nocturnal enuresis. They therefore hypothesized that passive smoking might impact children with PMNE because of a possible effect on bladder function and sleep.

A retrospective review of records for children with enuresis seen between February and December 2018 was undertaken; 81 patients with PMNE who had full medical data and appeared to be adherent to Desmopressin therapy were included in the study.

Demographic data, severity of symptoms, response to treatment with Desmopressin, sociocultural factors and smoking exposure, alongside sleep depth, snoring, past history of adenotonsillectomy and body mass index was recorded.

All the children were initially treated with 120mcg Desmopressin melts one hour prior to bedtime, with fluid restriction for one to two hours before bedtime. Those who had no, or partial response had their dose of Desmopressin increased to 240mcg after one month. All the children were evaluated after three months of Desmopressin.

The incidence of children wetting more than five nights a week was higher in the group exposed to smoke at home (86% compared to 65.7% who were not exposed). 90.9% of the eleven children who had less than 50% reduction in wet nights with Desmopressin were exposed to smoke. 60.8% of the twenty-three children who had between 50 and 99% reduction in wet nights with Desmopressin were exposed to smoke and 40.4% of the forty-seven patients who showed complete response to Desmopressin (i.e. were dry every night) were exposed to smoke.

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It was also noted that children who were wet more than five nights a week were more likely to have less than 50% reduction in wet nights than children who were wet 3-5 nights a week (46.7% v 21%). Treatment was found to be less successful in children whose parents smoked in the same room as them, but the number of cigarettes per day and sleeping in the same room as the smoker did not appear to have an impact.

Implications for practice The authors recognise that the study is limited by not considering the impact of factors such as constipation, obstructive sleep apnoea and nocturnal polyuria.

Investigations of the quality of sleep and of any sleep disorders were not undertaken. Compliance with Desmopressin treatment was based on family reporting only. Exposure to cigarette smoke was assessed on the number of cigarettes reported to be smoked daily and where they were smoked in relation to the child. Overall included numbers in the study were low.

This is the first published study that the reviewers have seen into the possible impact of passive smoking on enuresis in children. There are some large studies that highlight the potential effect of smoking on continence in adults, so it is not unreasonable to suggest that passive smoking may impact unfavourably on children with enuresis. This study indicates this might be the case.

It would be reasonable to discuss the potential impact of passive smoking on treatment resistance with the families of children who have enuresis. A reduction in exposure to cigarette smoke is likely to improve the general heath of both the child and their care givers as well as the possibility of improving Desmopressin response. Clinicians should therefore consider signposting parents and/or carers to local Stop Smoking services as appropriate.

Bladder & Bowel UK’s Free Downloadable Resources

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Bladder & Bowel UK have a range of booklets and leaflets 6 covering bladder and bowel problems in children and young people. Visit: https://www.bbuk.org.uk/children-youngpeople/children-resources/

The role of sleep pathology in the pathophysiology of nocturnal enuresis Pedersen MJ, Rittig S, Jennum PJ, Kamperis K Sleep Medicine Reviews 49 101228

Abstract The full pathophysiology of enuresis is complicated and unclear. Furthermore, the understanding of the effect of sleep remains uncertain. The authors aimed to review the findings of previous studies into the relationship between sleep and enuresis.

Different studies into the timing of bedwetting have produced differing and sometimes conflicting results. However, it is known that a longer initial period of uninterrupted sleep each night, prior to a wetting episode may help improve sleep quality and therefore quality of life.

Wetting can happen in any sleep stage, but happens most frequently in sleep stage N2 (25 – 62.5% of wetting incidents). Wetting in deep sleep varies from 13.6 – 50% of total episodes. Some studies report no wetting during REM sleep, with others citing up to 30% during this phase of sleep. The authors conclude that most wetting happens in N2 sleep or deep sleep with incidents in N1 stage and REM sleep being rare.

Some level of arousal has been detected prior to wetting and studies have found that bladder contractions result in a shift to lighter sleep in children with enuresis. This has led to the suggestion that children with enuresis may have their sleep disturbed by the bladder contractions and have transient arousals, with consequent sleep fragmentation and poor quality of sleep, which may interfere with the process that allows full waking.

Kirk et al (1996) suggested that healthy children were unable to wake after increased oral fluids before bed, causing wetting. Imada et al (1998) found that by the age of three most healthy children shifted to lighter sleep as their bladder filled and became dry at night before they were five years old.

Children who remained deeply asleep as the bladder filled were later achieving night-time continence, suggesting that ability to wake to a full bladder has a developmental element.

In 1997 Wolfish et al found that children who were dry at night were more likely to wake to auditory stimuli than children with enuresis. Other studies suggest that children with enuresis have more cortical arousals in sleep, but 7 this was not found by all researchers. It remains unclear whether arousal differences and sleep fragmentation are part of the mechanism of the enuresis or a consequence of it.

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However, a study by Soster et al (2017) showed that children with enuresis have different sleep microstructure from controls, which they argue may be as a result of sleep fragmentation and sleep deprivation and may result in reduced arousability.

Other studies show that children with enuresis and nocturnal polyuria do not have the same reduction in blood pressure at night as healthy controls and children without nocturnal polyuria. Heart rate at night has also been investigated by a number of studies, without clear conclusions.

Sleep disordered breathing may inhibit reduction in night time urine production; may affect natriuretic peptides and vasopressin production; it may increase sympathetic nervous activity and reduce parasympathetic activity as well as cause issues with sleep fragmentation. It is known that treatment of sleep disordered breathing may improve or resolve enuresis in children.

Many children experience an increase in bladder capacity at night. However, Yeung et al (2008) found that children with severe enuresis experienced bladder overactivity at night and had reduced nocturnal bladder capacity.

Since 1987 studies have shown that children with enuresis move more during sleep than controls. Periodic limb movement in sleep (PLMS) causes sleep disturbance due to cortical arousal and has been demonstrated in studies of children with enuresis. However, it is not yet clear whether PLMS are part of the pathophysiology of enuresis, whether they are due to bladder sensations disturbing sleep or unrelated.

Implications for practice There is increasing evidence that children with enuresis sleep differently to children who do not have enuresis, particularly in relation to increased cortical arousal and decreased sleep quality. This may affect their autonomic nervous system, impacting on blood pressure, heart rate and natriuretic peptide secretion and so causing increased urine production and nocturnal bladder overactivity.

Those working with children who have enuresis should consider whether sleep disordered breathing is an issue and if so, whether referral to ENT for assessment is appropriate.

Sleep hygiene may help to improve enuresis as well as quality of life. Families should be advised on strategies that may help to improve sleep. Treatment should not be delayed as improvement in enuresis may also help to increase sleep quality.

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High daily salt intake had a negative impact on how well nocturnal enuresis treatment worked on children aged 7-10 years Tsuji S, Yamaguchi T, Akagawa Y, Akagawa S, Kino J, Yamanouchi S, Kimata T, Kaneko K Acta Paediatrica (2020) 109, 193 – 197 Abstract Previous studies have demonstrated links between high salt intakes and/or high sodium excretion and resistance to treatment for enuresis with Desmopressin in children and to nocturia in adults. The authors therefore considered daily intake of salt in children with enuresis, estimated from spot urine samples collected each morning, and whether this affected their response to Desmopressin.

Eighty-nine children with enuresis who attended a University Hospital in Japan had urine samples collected at their first hospital visit and then for ten consecutive days.

39 children were considered to have an appropriate salt intake for age and 50 to have excessive salt intake, based on Japanese Ministry of Health, Labour and Welfare recommendations. All were treated with Desmopressin 120mcg melts.

The response to Desmopressin after one month for the group of children who had excessive salt intake was significantly worse than the response of the children who had an appropriate intake of salt.

The authors suggest that high salt levels may suppress the secretion of vasopressin from the pituitary gland or they influence the activity of vasopressin in the renal tubules. However, a previous study has suggested that high salt intake may increase vasopressin release. Furthermore, there is suggestion that high salt intake increase urinary sodium excretion and decrease response to Desmopressin.

Implications for practice This study has several limitations: the sample size is small, the exact daily salt intake was not measured, only early morning urine sodium was measured, which might be affected by excessive nocturnal diuresis, only Japanese children were included.

However, this study does appear to build on previous evidence that increased salt intake before bed can increase night-time urine production. It would therefore be worth considering whether overall daily intake of salt is within recommended limits for age, particularly in children who are not responding to first-line treatments for enuresis.

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Desmopressin use in pediatric nocturnal enuresis patients: is there a sex difference in prescription patterns Schroeder MK, Juul KV, Mahler B, Norgaard JP, Rittig S European Journal of Pediatrics 177 389-394

Abstract Desmopressin works on the V2 receptors in the kidney in the same way as the antidiuretic hormone, arginine vasopressin. It has been used to treat enuresis since the 1970s. Recently there have been reports indicating a difference in response to Desmopressin between genders, with adult women requiring lower doses than men.

The authors used the national drug monitoring database in Denmark to investigate how Desmopressin has been used in children with enuresis between 2004 and 2011.

40,596 children were identified as having used Desmopressin to treat enuresis since 2004. They were all included in an investigation of how often they were prescribed Desmopressin, at what dose, the strength of the formulation used and whether there was any other medication was taken at the same time.

It was found that: • There were no admissions to hospital with hyponatremia • Girls had a shorter duration of use of Desmopressin than boys for both tablets and melts • Most prescribing in Denmark adheres to treatment dose guidance, but 60mcg melts were used for enuresis in 19.8% of boys and 22.6% of girls • The percentage of girls and boys receiving the lowest doses of tablets (and spray before it was withdrawn) was similar • 19.7% of girls and 14.4% of boys had prescriptions for antidepressants at the same time as Desmopressin • More than half the children stopped taking desmopressin after three months prescriptions or less The authors hypothesise that as girls are more likely to have daytime wetting than boys, Desmopressin may be started later in the treatment course, so giving the appearance of a shorter duration of treatment.

Because of differences in prescribing of 60mcg melts they suggest that girls may have a greater sensitivity to Desmopressin than boys, as has found to be the case in adults.

However, the lowest dose available in the tablets (and in the spray before it was withdrawn) was likely to be too high for detection of any difference between genders.

It was thought probable that the prescribing of antidepressants is more likely to be as the result of combination treatment with imipramine and suggests that up to a fifth of Danish children may have required a combination of medication to treat enuresis.

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It is not possible to know if some children stopped Desmopressin after three or fewer prescriptions due to rapid improvement in enuresis or because of a lack of effect of the treatment.

Implications for practice Desmopressin appears to be a safe treatment for enuresis, with no incidents of hospitalisation in a large cohort of Danish children.

It is possible that some children, particularly girls respond to lower doses of melt (60mcg) than are currently recommended. Further investigation is required to see if there is a group of children for whom lower dose Desmopressin is sufficient to treat their enuresis and to examine whether there is a gender difference in Desmopressin response in children.

Bladder & Bowel UK’s Enuresis Award Have you, or your team, been innovative and made a difference to the care of children or young people with bedwetting? If so, we would like to encourage you to apply for the Bladder & Bowel UK Enuresis Award 2020.

For more information please visit: https://www.bbuk.org.uk/enuresis -award/

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Sharing Best Practice Training For more information about bespoke training email: bbuk@disabledliving.co.uk

Bladder & Bowel UK Annual Continence Symposiums Bolton 30th September 2020, Coventry 2021 date TBC More information available at: www.bbuk.org.uk/ professionals/ professionals-training/training-symposium/ Children’s Continence Special Interest Group To join email bbuk@disabledliving.co.uk Members receive email newsletters and information about training, developments and issues related to continence.

Free Downloadable Resources Available from the Bladder & Bowel UK website at: www.bbuk.org.uk

Editorial Group Dr Fiona Cameron (community paediatrician), Dr Paula Drummond (consultant community paediatrician), Dr Catriona Morrison (consultant paediatrician), Davina Richardson (children’s specialist nurse), June Rogers MBE (children’s specialist nurse), Martina Thomas (children's continence nurse), Dr Anne Wright (consultant paediatrician) Due to Covid-19 the articles in this edition have not been peer reviewed.

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Tel: 0161 607 8219 Email: bbuk@disabledliving.co.uk Web: www.bbuk.org.uk Bladder & Bowel UK, Disabled Living, Burrows House, 10 Priestley Road, Wardley Industrial Estate, Worsley, Manchester, M28 2LY Registered Charity No: 224742