Nocturia and Nocturnal Enuresis Chun-Hou Liao Chief, Division of Urology, Cardinal Tien Hospital Associate Professor, Fu-Jen Catholic University Adjunct

男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02

Nocturia and Nocturnal Enuresis

Chun-Hou Liao

Chief, Division of Urology, Cardinal Tien HospitalAssociate Professor, Fu-Jen Catholic UniversityAdjunct Attending, Department of Urology, NTUHSecretary-General, Taiwanese Continence Society (TCS) and Taiwanese Association of Andrology (TAA)



Nocturia Definition

◦ a bothersome condition, defined by the ICS as ‘‘the complaint that the individual has to wake at night one or more times to void

van Kerrebroeck P 2002 Nocturia that occurs twice or more per night can have a

substantial negative impact on the patient’s quality of life (QOL), mood and overall health

Nocturia can be caused by ◦ reduced bladder capacity◦ increased nocturnal urine volume

Multiple factors can contribute to nocturia, including polyuria, nocturnal polyuria, advanced age, sleep disorder, and bladder storage disorder including benign prostatic hyperplasia, overactive bladder, chronic pelvic pain syndrome.


1. Weiss et al. J Urol 2011;186:1358–1363; 2. Van Kerrebroeck et al. Neurourol Urodyn 2002;21:179–183

NP is a major cause of nocturia (76–88% of patients in 2 large cohorts)1

Defined as production of an abnormally large volume of urine during sleep:2

– Young: >20% of daily total output– Elderly: >33% of daily total output

NOCTURNAL POLYURIA


Mean variation in urinary excretion rate

ml/h

our

P<0.001

Adapted from Rittig et al. Am J Physiol 1989 Apr;256(4 Pt 2):F664-71.

Circadian Urine Production

Normal Enuresis

8AM-12AM 12AM-4PM 4PM-10PM 10PM-8AM


Circadian ADH Production

Mean variation in plasma antidiuretic hormone (ADH)

P a

vp (

pg/m

l)

P<0.001

Adapted from Rittig et al. Am J Physiol 1989 Apr;256(4 Pt 2):F664-71.

Normal Enuresis

8AM-12AM 12AM-4PM 4PM-10PM 10PM-8AM


NP is a major underlying factor which is often overlooked NP is a disease created by an impairment of natural circadian

rhythms of Arginine Vasopressin (AVP) NP may occur with other urological conditions, such as OAB

and BPO If NP is not treated when it occurs with OAB/BPO, nocturia will

persist

Myth: ‘Nocturia is only a symptom of some other underlying disorder, and is attributable to OAB in women, and BPO in men’

BUT

NOCTURIA TREATMENT OFTEN FAILS DUE TO QUESTIONABLE DIAGNOSTIC ASSUMPTIONS


Poor results are observed with OAB/BPO therapy for nocturia treatment

1. Johnson et al. J Urol 2003;170:145–148; 2. Djavan et al. Eur Urol Suppl 2005;4:61–68; 3. Johnson et al. J Urol 2007;178:2045–2050; 4. Yamaguchi et al. BJU Int 2007;100:579–587; 5. Brubaker & FitzGerald. Int Urogynecol J Pelvic Floor Dysfunct 2007;18:737–741; 6. Nitti et al. BJU Int 2006;97:1262–1266; 7. Rackley et al. J Urol 2006;67:731–736; 8. Kaplan et al. JAMA 2006;296:2319–2328


TURP FAILS TO IMPROVE NOCTURIA IN MEN

TURP is not the answer – other mechanisms (eg NP) involved

Reproduced from Urology, 61, Yoshimura et al. Nocturia and benign prostatic hyperplasia, 786–790. Copyright 2003, with permission from Elsevier


UNDERLYING NOCTURAL POLYURIA (NP) IS THE REASON WHY α1-BLOCKER TREATMENT OFTEN FAILS TO TREAT NOCTURIA

85% of patients unresponsive to α1-blocker treatment are found to have NP

Yoong et al. Med J Malaysia 2005;60;294–296

Global polyuria (10%)

Normal nocturnal output (5%)

NP (85%)


EVALUATIONClinicians should be alert to the potential

reluctance of patients to present their nocturia1Patients should be evaluated for underlying disease

states, cardiovascular conditions, consumption of beverages

Urine analysis, urine culture and cytology should be performed1

Questionnaires can quantify the effect of nocturia on daily functioning

Frequency–volume charts (FVCs) are a key tool for diagnosis of NP


VALUE OF FVCS FOR APPROPRIATEDIAGNOSIS AND TREATMENT

FVCs provide valuable information regarding voiding frequency and urinary volumes for 24–72 hours

Chart can also include record of volume and type of fluid ingested, time of retiring to bed and time of rising

If nocturnal urine volume >20–33% of total 24-hour urine volume, NP is present

Patient 1 Patient 2 Patient 3

24-hour volume 1900 mL (no global polyuria)

5000 mL 2500 mL(no global polyuria)

Nocturnal urine volume(includes first morning void)

1200 mL 1500 mL 1500 mL

Nocturia episodes 3 3 7

Nocturnal urine volume/24-hour volume

63% (NP)

30%

(normal)

60%

(NP)

Maximum voided volume

400 600 200

Diagnosis NP Global polyuria Mixed aetiology(NP and reduced voided volumes)

VOIDING DIARY ANALYSIS: CASE STUDIES


Simple Algorithm for Classification and Treatment of Nocturia

Medical historyExamination

Laboratory tests

FVC

Dietary advice

Lifestyle adviceExclusion/treatment of OSA

Desmopressin (<65 years)

Endocrinologist

Poly-dipsia

DI/DM/other

Urologist, uro-gynaecologist, geriatrician, sleep expert

24h - polyuria(24-hour voided volume

>40 mL/kg)

NP(nocturnal urine

volume >20–33%, including first morning

voided volume)

Apparent bladder storage problems

BPOOAB

Bladder dysfunction

OtherSleep problems

CardiacGynaecological

α1- blockersanticholinergics

FVC, frequency–volume chart; DI, diabetes insipidus; DM, diabetes mellitus; OSA, obstructive sleep apnoea


ManagementLifestyle modificationLifestyle modification is recommended as the first-

line option◦ van Kerrebroeck P 2010

These recommendations include ◦ preemptive voiding immediately before going to bed◦ nocturnal ‘‘dehydration,’’ ◦ dietary and fluid restrictions (avoidance of caffeinated

beverages and alcohol)◦ medication timing (taking diuretics in the afternoon)◦ evening leg elevation to mobilize fluids, and use of

sedatives◦ Weiss JP 2011


ManagementLifestyle modification A prospective study of 56 patients of nocturia managed by

nondrug lifestyle measures including restriction of fluid intake, refraining from excess hours in bed, moderate daily exercise and keeping warm in bed

Their results showed mean nocturnal voids and nocturnal urine volume decreased significantly from 3.6 to 2.7 (p <0.0001) and from 923 to 768 ml (p = 0.0005), respectively.

More than 50 % patients showed an improvement of more than 1 episode

Soda T 2010


ManagementLifestyle modification Pelvic floor exercises are thought to be effective to treat urgency

at night [Johnson II TM 2005]. However, no randomized control trials (RCT) evaluating

behavioral therapy to treat nocturia as a primary outcome is available.

One trial enrolled 49 men with nocturnal polyuria and compared furosemide intake 6 hour before bedtime with placebo

Using 7-day FVC, administration of 40 mg of furosemide 6 hour before bedtime was superior to placebo in reducing the numbers of nocturnal voids, but not the nocturnal voided volume.

◦ Reynard JM 1998


WHAT IS DESMOPRESSIN?

• Desmopressin is a synthetic analogue of AVP• Natural AVP is secreted from the pituitary gland

and acts on the distal renal tubules and collecting ducts to promote water reabsorption

• Insufficient AVP in the kidneys or renal AVP resistance can increase urine production and cause NP/nocturia

• Desmopressin increases water reabsorption in the distal and collecting tubules of the kidney, concentrating urine and decreasing urine output and nocturia

Van Kerrebroeck et al. Eur Urol 2007;52:221–229


Desmopressin has Level 1b-Evidence andGrade A-Recommendation


Weiss et al. BJU Int 2011;108:6–21

COMBINATION THERAPY Daytime LUTS are treated with

anticholinergics and α1 blockers. Night-time LUTS (nocturia) may

have multiple underlying causes If patients have more than one

cause underlying nocturia, all must be treated

Desmopressin is only agent which addresses aetiology of nocturia due to NP

Combination therapy can address daytime and night-time LUTS


Desmopressin Anticholinergic α1-blocker+ +

Desmopressin Anticholinergic+

Desmopressin α1-blocker+

Anticholinergic α1-blocker+

Further investigational studies of these strategies are warranted

Possible therapy combinations

21


Poor results are observed with OAB/BPO therapy for nocturia treatment

BPO/OAB therapy Net advantage vs placebo (reduction in number of voids

or % reduction)

BPO Terazosin1 0.3 voids

Tamsulosin OCAS2 0.3 voids

Doxazosin + finasteride3 ~0.2 voids

OAB Solifenacin4 0.16 voids

Solifenacin5 0.08 voids (NP)

0.18 voids (No NP)

Tolterodine ER6 ~0.75 voids/week (severe urgency nocturnal voids only)

Tolterodine ER7 4%

BPO + OAB Tolterodine ER + tamsulosin8

Combination therapy

0.2 voids

1. Johnson et al. J Urol 2003;170:145–148; 2. Djavan et al. Eur Urol Suppl 2005;4:61–68; 3. Johnson et al. J Urol 2007;178:2045–2050; 4. Yamaguchi et al. BJU Int 2007;100:579–587; 5. Brubaker & FitzGerald. Int Urogynecol J Pelvic Floor Dysfunct 2007;18:737–741; 6. Nitti et al. BJU Int 2006;97:1262–1266; 7. Rackley et al. J Urol 2006;67:731–736; 8. Kaplan et al. JAMA 2006;296:2319–2328

OCAS, oral-controlled absorption system; NP, nocturnal polyuria; ER, extended release

22


DESMOPRESSIN + α1 ANTAGONISTS DECREASE NOCTURIA AND IMPROVE IPSS SCORES IN PATIENTS WITH LUTS

Observational study of patients with LUTS suggestive of BPH and nocturia

Treated with desmopressin tablets for 3 months 34 patients with diagnosed NP receiving an α1 antagonist at

least 4 weeks prior to desmopressin treatment Addition of desmopressin associated with:

◦ 50% reduction in median nocturia episodes (from 4 to 2)◦ Reduced median IPSS score (from 18 to 14)

Berges et al. ICS/IUGA, 23–27 August 2010, Toronto, Canada. Abstract 75

Desmopressin provided additional benefit to patients with LUTS

suggestive of BPH and nocturia already receiving α1 antagonist


DESMOPRESSIN + LUTS AGENTS ARE AN EFFECTIVE TREATMENT FOR NOCTURIA IN PATIENTS WITH BPH Patients with BPH >65 years with nocturia and NP All treated with α-blocker; ~33% on anticholinergics Clinical response (decrease ≥2 voids) was achieved by 61.4%

patients (p<0.001 relative to placebo)

Reprinted from J Urol, 185, Wang et al, Low dose oral desmopressin for nocturnal polyuria in patients with benign prostatic hyperplasia: a double-blind, placebo controlled, randomized study, 219–223., Copyright 2011, with permission from Elsevier

Reduction in number of nocturnal voids over time

Increase in duration of first sleep period over time

0

4

Me

an

nu

mb

er

of

no

ctu

rna

l vo

ids

1

6

8

2

3 6Time (month)

Baseline 12

Placebo n=58Desmopressin n=57

0Me

an

du

ratio

n o

f fir

st s

lee

p p

erio

d (

min

)

1

100

150

50

3 6Time (month)

Baseline 12

Placebo n=58Desmopressin n=57


DESMOPRESSIN + LUTS AGENTS ARE A WELL TOLERATED TREATMENT FOR NOCTURIA IN PATIENTS WITH BPH

No serious systemic complications were found during medication

Serum sodium level of desmopressin group was always lower than the placebo group, but no clinically significant symptoms seen

Wang et al. J Urol 2011;185:219–223

Adverse event Placebo (% patients)

Desmopressin (% patients)

Headache 6.9 5.3

Dizziness 6.9 7.0

Nausea 1.7 0

Serum sodium <130 mmol/L without clinical symptoms

17.2 15.8


Practical Considerations for Desmopressin Use

Initiate at low dose (0.1 mg/day – before sleeping) Increase dose weekly until maximal efficacy

reached Maximum recommended dose: 0.4 mg/day Patients should avoid drinking fluids 1 hour before

and 8 hours after administration In men ≥65 years, desmopressin should be avoided

if serum sodium concentration below normal In other men ≥65 years, measure serum sodium at

day 3 and 7, and 1 month. If all readings normal, then monitor every 3–6 months


SUMMARY: CURRENT DIAGNOSIS AND TREATMENT RECOMMENDATIONS

Nocturia is a condition which requires careful diagnostic evaluation

FVCs are a valuable diagnostic toolDesmopressin is recommended as first-line treatment for

nocturia related to NP◦ Mono- or combination therapy

A significant treatment effect should be an improvement in all symptoms clinically associated with nocturia

Further research is needed to validate and clarify clinical relevance of definition of nocturia and NP◦ Definitive, relevant sleep endpoints for nocturia studies are

required


Nocturnal Enuresis


Nocturnal EnuresisEnuresis – piss-a-beds (Greek)Enuresis – A normal void occurring at an

inappropriate or socially unacceptable time or place

Nocturnal enuresis – Children void in bed while asleep and are generally not aroused by the wetting

Monosymptomatic with a familial tendency


Quantification of Nocturnal EnuresisAge: children over the age of 5 yearsFrequency: number of wet nights per week

or month; the time of wetting at early (first 2 hours) or late (2 hours before arising) or randomly timed

Amount of wetting: The bed is soaking wet or smaller amounts

Arousibility: To wake up to a full bladder


Subtypes of Nocturnal EnuresisPrimary nocturnal enuresis: mono-

symptomatic bedwetting never have been dry for uninterrupted period >6months

Onset nocturnal enuresisFamilial nocturnal enuresisNocturnal polyuria enuresis : urine

production > functional bladder capacity on wet nights, nocturia on dry nights


Epidemiology of Nocturnal Enuresis15 – 20% of 5-year-olds, 5% of 10-year-

olds, 2-3 % of all adolescents wet the bed at least 1/month

Enuresis has a 15% per year spontaneous resolution rate

Bed wetting is the cause of significant psychosocial stress, especially in older children


Balance between Bladder capacity and Nocturnal urine vol


Causes of Enuresis

Urine VolumeUrine VolumeBladder

ContractionsBladder

Contractions

Sleep ArousalSleep ArousalENURESISENURESIS

Adapted from Wolfish et al., J Urol 2001; Vol. 166, 2444–7.

Causes of Enuresis: A Triad1


Treatment of Nocturnal EnuresisConditioning therapy: Alarm system or

dry-bed training,effective in about 30-80%Medcal therapy: (1) Tricyclic

antidepressant (TCA), imipramine, amitriptyline effective in 10-50% (author 24%)

(2) anti-cholinergics (3) desmopressin (DDAVP)Side effect in combination medical

therapy


DDAVP Therapy in Nocturnal Enuresis in ChildrenDDAVP in dose of 10-20 ug intranasally is

effective in 70% of children with PNEAfter discontinuing DDAVP for 3months,

21% remained dry without medication20 ug is adequate in treating PNE, in

children not responded to 20ug, 40ug did not effective

No serious adverse effect


Thanks for your attention

Documents

Nocturia and Nocturnal Enuresis Chun-Hou Liao Chief, Division of Urology, Cardinal Tien Hospital Associate Professor, Fu-Jen Catholic University Adjunct