nocturia and nocturnal enuresis chun-hou liao chief, division of urology, cardinal tien hospital...
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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)
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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.
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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%)
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Desmopressin has Level 1b-Evidence andGrade A-Recommendation
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Desmopressin Anticholinergic α1-blocker+ +
Desmopressin Anticholinergic+
Desmopressin α1-blocker+
Anticholinergic α1-blocker+
Further investigational studies of these strategies are warranted
Possible therapy combinations
21
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Nocturnal Enuresis
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Balance between Bladder capacity and Nocturnal urine vol
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
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
男性健康學園 NTU MEN‘S HEALTH ACADEMY – 2015-08-02
Thanks for your attention