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Markos Karavitakis

Definition
Nocturia is the complaint that the individual has to wake at night 1 or more times to void with each voided preceded and followed by sleep (1). Several authors suggest that nocturia should not be considered only as a complaint but rather as a disorder which can be caused by serious underlying conditions (2). Although traditionally considered by the clinicians as a part of the constellation of the lower urinary tract symptoms mainly due to overactive bladder syndrome or benign prostatic hyperplasia, it is now emphasized that nocturia should be regarded as an autonomous clinical entity (3).

Epidemiology
Nocturia is a very common condition affecting both younger and older individuals. The prevalence of nocturia has been estimated as follows (4):
  • Men aged 20-40 years: 2-17%
  • Women aged 20-40 years: 4-18%
  • Men aged >70 years: 29-59%
  • Women aged >70years:28-62%
Despite its prevalence and impact on quality of life, most people affected from nocturia do not seek medical assistance because they consider it as a condition associated with ageing or because they feel embarrassed (5).

Etiology/pathophysiology
There is a circadian control of urine production which is established at nearly 7 years of age. Based on this circadian rhythm, urine production during the day is 2 to 3 times more than that of the night. This difference is mainly due to the difference in the production of arginine vasopressin at night (6).
Antidiuretic hormone (ADH) is produced on the posterior pituitary and increases water reabsorption at the renal collecting tubule. There is a physiologically increase of ADH at night time leading to reduced volumes of concentrated urine during sleep. This circadian rhythm in elderly people is altered with reduced levels of ADH at night. This observation can partially explain the higher prevalence of nocturia in the elderly population. Indeed, there is a normal modification of this circadian rhythm nearly at the age of 60 years when the nightly production of urine starts to increase (7).
Pathophysiologically nocturia is the result of the disproportion between nocturnal urine volume (NUV) and functional bladder capacity (which can be lower at night).
Nocturnal urine volume is the total urine volume from voids after going to bed (with intention to sleep) and includes the first void at the time of waking (with intention to rise). In the definition of nocturnal urine volume is excluded the last void before sleep (8). Functional bladder capacity is expressed through the maximal voiding volume (MVV).
Nocturia can result from 4 main causes:
a) overall increase of urine production (24h-polyuria)
  • 24h polyuria is defined as¨>40 ml/kg urine production
  • Causes of 24h polyuria include
    • diabetes mellitus
    • diabetes insipidus
    • primary polydipsia
    • hypercalcemia
    • drugs (tetracycline, lithium, diuretics etc)
b) increased urine output only at night (nocturnal polyuria)
  • Nocturnal polyuria occurred when nocturnal urine volume is higher than 20-33% of total urine volume (1)
  • This definition has been recently challenged by the authors of the well-known Krimpen study (9). The authors of this study defined nocturnal polyuria as the condition of producing urine at a minimal rate of 90 ml/h during the night time (from 1:00 am to 6:00 am)
  • Causes of nocturnal polyuria include:
    • excessive production of atrial natriuretic peptide
    • abnormal endogenous production of arginine vasopressin hormone by the posterior pituitary
    • medications ie diuretics, steroids
    • nighttime drinking
    • renal tubular dysfunction
    • obstructive sleep apnea
c) reduced bladder capacity
  • Nocturia might be a result of disproportion between nocturnal bladder capacity and quantity of urine entering the bladder at night
  • Can be permanent or nocturnal and functional or anatomic
  • Causes of reduced bladder capacity include:
    • post voiding residual volume due to bladder outlet obstruction
    • overactive bladder
    • any pathologic condition leading to reduced anatomic capacity (ie bladder cancer, interstitial cystitis, radiation cystitis) or extrinsic compression
d) Sleep disorders
  • Any condition that causes sleep disorder can also lead to nocturnal voiding when patient is awake and nocturia
  • Causes of sleep disorder include:
    • primary sleep disorder (insomnia, arousal disorders)
    • secondary sleep disorders (ie chronic obstructive pulmonary disease, cardiac failure etc)
    • psychiatric conditions (Parkinson disease, dementia etc)
    • medications (ie corticosteroids, diuretics etc)
Nocturia index is calculated as NUV divided by MVV and is positive when >1.
For example, we consider a man with MVV of 400 mL and his NUV of 1200ml. We would expect that he would void 3 times at night, including the early morning void. Reasonably, we would expect him to wake up 2 times at night to void. This number is called as predicted number of nightly voids (PNV) and is defined as nocturnal index minus 1. When the actual number of voids exceeds the predicted number of nightly voids, it suggests that nocturia occurs at volumes less than maximal voiding volume which mandates an evaluation of the urinary tract (10).
Risk factors
There are several risk factors associated to the development of nocturia:
  • Age: older age is associated with increased risk (11)
  • Gender: women have higher risk of nocturia (4)
  • Ethnicity: African are associated with higher risk (12)
  • Metabolic syndrome, obesity and hypertension (13)
  • Low testosterone levels (14)
  • In men, the most common predictive factors are: urinary urgency, benign prostatic hyperplasia and sleep disruption while in women are urgency, obesity and snoring (15)
  • body mass index (16)
  • alteration in bowel habits and more precisely hard and infrequent stooling (17)
Consequences of nocturia
  • Nocturia severely affect patient’s quality of life because of reduced quality of sleep (18)
  • Nocturia is considered one of the most bothersome lower urinary tract symptoms (19)
  • The higher the number of nocturia episodes the higher the degree of bother caused from nocturia (20)
  • Nocturia has been associated with diurnal fatigue, concentration difficulties and accidents (21)
  • Nocturia increases the risk of fall and hip fractures in older men (22)
  • The risk of hip fracture increase with nocturia frequency, the odds ratio for a hip fracture is 1.36 in men having >/=2 voids at night and 1.8 in those man having more than 3 voids at night (23)
  • Nocturia increases the risk of an incident fall by 25% over 3 years (24)
  • The risk of fall increases with the night time voiding, the odds ratio of falling increase from 1.84 with 2 voids/night to 2.15 with 3 voids/night (25)
  • Nocturia has been established as risk factor for coronary heart disease and death (26)
  • Nocturia has been linked to depression and endocrine, immune, and metabolic disorders (27)
  • Nocturia has been considered as an independent risk factor of mortality in younger and older patients (28)
  • Nocturia has been linked with hypertension, obesity and glucose intolerance (29)
  • Nocturia as a cause of disrupted sleep may lead to (30):
    • Reduced concentration of thyrotrophin
    • Increased evening cortisol concentration
    • Increased activity of sympathetic nervous system
    • Reduction of tolerance of glucose
    • Decreased plasma levels of leptin
    • nocturia has also a significant negative impact on the partners and caregivers of affected persons, which is demonstrated by the higher rates of depression and chronic illness of these individuals (31)
    • the economic impact of nocturia is also very important. Nocturia , mainly moderate to severe is associated with a substantial increase in health care costs, higher number of hospitalization days, and higher inpatient and outpatient medical costs (32)
    • nocturia also negatively impact on work productivity. It is estimated that nearly 61 billion dollars /year is the loss of productivity from nocturia in the population aged <65 years. Additionally, the cost due to the the falls of people affected from nocturia is estimated as 1.5 billion per year (33)
Clinical evaluation
As previously stated, affected patients are often reluctant to discuss their symptoms. Therefore, physicians should enquire and specifically ask about nocturia and discuss with their patients. Many patients complain of fatigue related symptoms and not of nocturia.
Initial evaluation should include a detailed history of patient symptoms focusing on urological history, previous surgeries, medication use, alcohol use and sleep disturbances.
History of neurological, cardiovascular and pulmonary disease should be documented.
A thorough clinical examination should be always performed. In women, prolapse should be recognized because nocturia can be seconday to incomplete bladder emptying.
Frequency volume (FVC) chart is the most important tool for the initial evaluation of nocturia (1).
In FVC, patients record the volume and the time of daytime and night time void for 1 to 3 days. The information obtained from FVC can guide clinician regarding aetiology and management.
FVC can also include additional information such as start and end of sleeping and time, type and volume of fluids ingested. When these additional information are included, FVC is called bladder diary.
Frequency volume chart is considered more precise than the question of nocturia on IPSS (34).
Bladder diary permits the classification of patients as those having global polyuria, nocturnal polyuria and reduced bladder capacity.
More detailed evaluation of nocturia can be done by using validated questionnaires such as Nocturia quality of life questionnaire (35).
Several tools evaluating the quality of sleep can also be used (ie Medical Outcomes Study Sleep scale) (36).
Urine analysis and culture should be done to detect infection and diabetes insipidus.
Cytology and other investigations should be carried out when indicated and clinically appropriate.

Management
The most important point in the decision making process and the management of nocturia is the identification of the underlying cause. This would allow specific treatment. Variables that are associated with successful treatment of nocturia include: reduction in the number of nocturia episodes, increased time to first awakening, increased total daily sleep time, improvement of quality of life and reduction in comorbidities (37). A combined approach including behavioral and medical interventions might also be of benefit in some patients.
1) Conservative measures
Initial approach should include lifestyle measures and preventive activities including:
  • Preemptive voiding before going to bed
  • Fluid restrictions (ie alcohol and coffee)
  • Modification of timing of medication such as diuretics in the aftermoon
  • Particular attention should also be focused on the sleep environment with attention on room temperature, noise, lighting and consistent times of going to bed (38)
  • Exercise in a regular way might provide a deeper sleep and increase the bladder volume arousal threshold (39)
  • Patients affected from peripheral edema might found useful elevate their lower limbs before going to bed (40)
  • Sedatives and short acting hypnotics might be useful in cases with more severe sleep disorders (39)
2) Medical management
  1. α 1 blockers (41-45)
  • several a1 blockers including tamsulosin, doxazosin have been assessed with conflicting results
  • Despite statistically significant improvements in symptoms, the clinical significance of these results are questionable
  1. Antimuscarinics (46-51)
  • Since there is a common association between overactive bladder and nocturia, it has been proposed that medications acting on overactive bladder will have beneficial effect on nocturia.
  • However, the evidence supporting the use of antimuscarinics for the treatment of nocturia is low.
  • Yet, as nocturia is multifactorial, it would be expected that antimuscarinics would have the maximum effect in those cases of nocturia associated with severe urgency.
  1. Anti-inflammatory medications
  • anti-inflammatory medications that have been studied for the treatment of nocturia include celecoxib (52) and diclofenac (53)
  • both studies favored the use of NSAID for the management of nocturia but the effect size was weak
  1. melatonin
  • Melatonin has been studied for the treatment of nocturia but the results were poor (54)
  1. Desmopressin (55-59)
  • desmopressin is the most used drug for the treatment of nocturia
  • In some countries, antidiuretic therapy is the only pharmacological medication indicated for nocturia
  • Desmopressin is a synthetic analogue of vasopressin, an agonist of the V2 receptors which are found on the distal collecting tubules.
  • Activation of the V2 receptors increases the concentration of the urine.
  • Contrary to vasopressin, desmopressin is a selective V2 receptor agonist thereby avoiding the vasopressor and uterotonic effects of V1 activation.
  • Additionally, desmopressin is more powerfull and has more prolonged half life than vasopressin.
  • Desmopressin is specifically useful in cases of nocturia due to aged related nocturnal polyuria and due to diabetes insipidus.
  • It is still unclear whether antidiuretic therapy should be limited only for patients with FVC demonstrated nocturnal polyuria or should also include all patients with nocturia aiming to regulate nocturnal urine production with nocturnal bladder capacity.
  • There are several ways of administration of desmopressin: intranasal spray, oral tablets, orally disintegrating tablets. Oral desmopressin is used at doses of 0.1, 0.2 and 0.4 mg.
  • Appropriate concentrations of melt formulations are 60, 120, and 240 mg fast disintegrating oral preparation.
  • Several studies evaluating the efficacy of desmopressin demonstrated the superiority of this medication comparing with placebo in reducing the number of nocturnal voids, in improving the duration of sleep until the first nocturnal void and in meliorating the quality of life.
  • Several studies have shown that the tolerability profile of desmopressin is good with hyponatraemia as the only potentially serious adverse event
  • The risk of hyponatriaemia increase with age, being higher in patients >65 years old with lower baseline levels of sodium.
  • Other, minor adverse events include headache and nausea.
  • Contraindication to antidiuretic therapy includes patients with polyuria of unknown origine, baseline hyponatriemia or patients with significant reduction of sodium (from normal to lower limits of normal after initial administration of antidiuretic treatment.


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