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

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