What is the key to treat nocturia and nocturnal enuresis? · voids/night is a ‘threshold’ for significant negative impact from nocturia If treatment can reduce nocturia frequency
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What is the key to treat nocturia and nocturnal enuresis?
Antonella Giannantoni
Department of Urology and Andrology
University of Perugia, Italy
Rome, June 25-26, 2015
ANTONELLA GIANNANTONI
DISCLOSURE
ALLERGAN, ASTELLAS, MENARINI
NOCTURIA
Definition: voiding during (nocturnal) sleep time
• Preceded and followed by sleep (ICS guidelines)
Normal: nocturia 1 void/night
van Kerrebroeck et al Neurourol and Urodyn 2002
Gender (age range) Prevalence
Men (20–40 years) 2–17%
Women (20–40 years) 4–18%
Men (>70 years) 29–59%
Women (>70 years) 28–62%
Nocturia: prevalence (≥2 voids/night)
Meta-analysis of 43 studies
NOCTURNAL ENURESIS
Definition: intermittent involuntary voiding during sleep in a child aged 5 years or more
A minimum of one episode a month for at least three months is required for the diagnosis to be made
Monosymptomatic nocturnal enuresis (MNE)
Nonmonosymptomatic nocturnal enuresis (NMNE)
Age range Prevalence
5 years old 8-20%
10 years old 1.5-10%
adults 0.5-2%
7.5 years old 2 or more times/wk Neveus et al. J Urol 2010
Classification
1. Nocturnal Polyuria (NUV
>20-33% by ICS guideline
criterion)
Krimpen study: proposes
NUV cutpoint >90 ml/hr
sleep
2. Decreased bladder capacity
3. Mixed
4. Global polyuria (24-hour
output >40 ml/kg)
Nocturnalpolyuria
lack of the normal
nocturnalincrease in vasopressin
secretion
Rittig et al. Am J Physiol 1989
Nocturnaldetrusor
overactivity
Yeung et al. J Urol1999
Lack of inhibition of
bladder emptying
during sleep
Problems in sleep
mechanisms and arousal
Lottmann et al. Int J Clin Pract 2007
Nocturia Nocturnal Enuresis
Results from studies ofmortality, fractures andQoL all show ≥2voids/night is a ‘threshold’for significant negativeimpact from nocturia
If treatment can reduce nocturiafrequency to <2 voids/night onaverage, risks and bother topatients may be significantlyreduced
There is a large grey zone between MNE and NMNE:
Many children assumedto have MNE are found
to have NMNE
The pathogenesisoverlaps between the 2
conditions
The evaluation and treatment of the 2
conditions may havesimilarities
Less than half of all bed wettingchildren are truly monosymptomatic
What degree of nocturia isimportant
Nocturia is a multifactorial condition
Urological
evaluation
reveals:
Nocturnal polyuria Reduced nocturnal
bladder capacity
24-hour polyuria
Definition: Nocturnal urine volume
>20–30% of total 24-hour
urinary volume (dependent
on age)
Urine production within
normal limits; increased
frequency, small voided
volumes
24-hour urinary
output exceeding
40 mL/kg body
weight
Possible causes: • Impaired circadian
rhythm of AVP secretion
•Congestive heart failure
•Renal insufficiency
•Excessive evening
fluid/caffeine intake
•Diuretic medication
•Oestrogen deficiency
•Sleep apnoea
•Venous insufficiency
•Oedema
•Hypoalbuminemia
•Overactive bladder
•Bladder outlet obstruction
(e.g. BPH)
• Infection
• Interstitial cystitis
•Bladder hypersensitivity
•Calculi
•Cancer
•Neurogenic DO (e.g. MS,
Parkinsons’ disease)
•Poorly-controlled
diabetes mellitus
(type 1 or type 2)
•Diabetes insipidus
•Polydipsia
Van Kerrebroeck P. Curr Opin Obstet Gynecol 2011
1. Abrams et al. Neurourol Urodyn 2004; Weiss et al. J Urol 2011 3. Chang et al. Urology 2006
Europe1
n=845
NP Without NP
74%
26%
Asia3
n=41 (males only)
83%
17%
USA2
n=934
12%
88%
Nocturnal polyuria is present in the majority of nocturia patients
The kidneys, rather than the bladder, have a key role in nocturia
Falls
Fractures
Significant decrease in HRQoL
Sleep deprivations
Parsons et al. BJU Int 2009
Temml et al. Neurourol Urodyn 2009
Nakagawa et al. J Urol 2010
Nocturia-induced complications
Primary evaluation
It should focus on void habits:
urgency, day-time incontinence,holding maneuvers (standing ontiptoe, pressing the heel into theperneum), micturition symptoms
About bed wetting:
How often does it occur, every nightor only sporadically? Has the childalways been wetting? Does the childalso have nocturia?
Family history, general symptoms, bowel function, psychiatriccomorbidities (attention deficit hyperactivity disorder)
A good case history is the cornerstone of both evaluations
Presence of other LUTS or OAB
ComorbiditiesDM, Diabetes Insipidus, hearth diseases, pulmonary diseases, kidney diseases
Pharmachological agents
Disturbed sleep and insomnia
Depression and anxiety disorders
Snoring
Pruritus
Nocturnal Enuresis Nocturia
Primary evaluation: important aspects of the physical examination of a child with NE
Di Bianco et al, Avicenna Med J 2014
Nocturia and NE: frequency-volume chart/bladder diary
1. It helps detect children with NMNE
2. It provides prognostic information
3. It detects children who requireextra-examination
Fluid intake and voided volume should be measured for at leasttwo days
Enuresis, daytime incontinence and other bladder related symptoms
Bowel movements
Assessment of nocturnal urine production (weighing diapers)
Neveus et al. J Urol 2010
Frequency of voids and voided volumes for a period of 3 days
Episodes of urgency and incontinence
Time of going to bed to go to sleep and the time of getting up to start a day’s activities
Reason for voiding(normal desire, urgency, pre-emptive for fear of urgency or urinary incontinence or convenience)
Measurement of nocturnal urine production
Cornu et al. Eur Urol 2012
A correct assessment is the key to effectively
treat Nocturia and Nocturnal Enuresis
NE and nocturia treatment: general lifestyle advice
It should be given to all bed wettingchildren
It has an independent therapeutic effect(grade Ib evidence)
Instruct the family to keep a calendar ofdry and wet nights
Nocturnal polyuria: minimize eveningfluid and solute intake (flexible)
Void regularly during the day
Liberal fluid intake during the day(expecially during the morning and early afternoon hours)
It should be given to all patients withnocturia
Physical activity
Pre-emptive voiding before sleep
Evening- and night-time fluid restriction
Avoidance of caffeine and alcohol excess
Afternoon/evening leg elevation and wearing of compression stockings during the day
Treatment of sleep apnoea
OAB/BPH therapies have limited effect on nocturia
BPH/OAB therapy Net advantage vs. placebo
(reduction in number of voids
or % reduction)
BPH
Terazosin 1 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)
BPH + OABTolterodine ER + tamsulosin 8
Combination therapy
0.2 voids
1. Johnson et al. J Urol 2003;:2. Djavan et al. Eur Urol Suppl 2005; 3. Johnson et al. J Urol 2007; 4. Yamaguchi et al. BJU Int 2007; 5. Brubaker & FitzGerald. Int Urogynecol J Pelvic Floor Dysfunct 2007; 6. Nitti et al. BJU Int 2006; 7. Rackley et al. J Urol 2006; 8. Kaplan et al. JAMA 2006
OCAS, oral-controlled absorption system; NP, nocturnal polyuria; ER, extended release
Desmopressin: mechanism of action
Desmopressin is a selective V2-receptor agonist:
Retains the antidiuretic properties of vasopressin
Lacks the unwanted pressor activity of vasopressin
When bound to V2-receptors in the kidney, it:
Increases tubular water permeability
Enhances water reabsorption
Urine becomes more concentrated
Vilhardt H. Drug Investigation 1990 Hammer M & Vilhardt H. J Pharmacol Exp Ther 1985
Dose (µg)Dec
reas
e in
no
ctu
rnal
uri
ne
volu
me
(mL)
0
100
200
300
400
0 20 40 60 80 100
*
Male
Female
Increased age and female gender are well-known risk factors for the
development of desmopressin-induced hyponatremia
The decrease in nocturnal urine volume in nocturia patients treatedwith desmopressin over 28 days was significantly larger for women atthe lower desmopressin melt doses
Desmopressin: results & grades and levels of recommendations
In Abrams et al. 4th International Consultation on Incontinence 2009 Abrams et al. Neurourol Urodyn 2010Schröder et al. European Association of Urology 2010Thüroff et al. Eur Urol 2011;59: 387-400Oelke et al. © European Association of Urology 2011
16
Nocturia patients experience significant and clinically meaningful reduction in night-time voiding and prolongation of initial sleep period with short-and long-term desmopressin treatment
Desmopressin is well tolerated in the short- and long-term; cessation causes nocturia severity to revert to baseline at 1 year
Both patient QoL and productivity at work improve with desmopressintreatment
ICI: Grade A (level 1)
EAU: Grade A (level 1b)
Address daytime
symptoms
• anticholinergic
• a1-blocker
• combinations
Example of a potential simple algorithm to differentiate night-time urination
LUTS, lower urinary tract symptoms; BPO, benign prostatic obstruction; 5-a RI, 5-alpha reductase inhibitor
Daytime LUTS
(predominantly
daytime symptoms)
Night-time LUTS
(predominantly
night-time
symptoms)
OAB BPO BPO and OAB
anticholinergic • a1-blocker
• 5-a RI
• combination
• outlet reducing
surgery
desmopressin
Mixed LUTS
(mixed daytime and
night-time symptoms)
Persistent
night-time
symptoms
desmopressin
LUTS / NOCTURIA
• Exclude and treat non-urological causes
(such as cardiac, OSA)
• Lifestyle changes
a1-blocker +
anticholinergic
17
18
TreatmentLevel of evidence
Grade of recommendationPharmacological treatments
Antidiuretics (desmopressin) 1 A
Desmopressin + alarm combination
1 A
Tricyclic antidepressants 1 C (cardiotoxicity)
Anticholinergics 2 B
Conditioning treatments
Alarm 1 A
Dry bed training 2 D
Arousal training 3 C
RECOMMENDATIONS FOR THE TREATMENT OF BEDWETTING
Abrams et al. Neurourol Urodynam 2010Tekgül et al. Guidelines on Urinary Incontinence 2011
ICI recommendations
EAU/ESPU recommendations― Antidiuretics (desmopressin): Level 1, Grade A― Alarm treatment: Level 1, Grade A― Imipramine: Level 1, Grade C (cardiotoxicity)
Active treatment should usually not bestarted before age 6
years
ENURESIS TREATMENT: Alarm therapy
It should be considered in every child with NE, (expecially in those
with well motivated parents) Glazener et al. 2007
Grade Ia evidence
It is presumed to cure NE due to condition effects on arousaland/or by increasing nocturnal bladder reservoir function
Butler et al. Scand J Urol Nephrol 2007; Oredsson et al. J Urol 1998
Therapy requires a minimum of 2 to 3-month trial
It should be continued until at least
14 consecutive dry nights are achieved
Practical consensus guidelines for the management of NE
A B
Van de Valle Eur J Paediatr 2012
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