Impact of nocturia: falls, fractures, mortality, and productivity

Sleep disturbance has been associated not only with increased bother and impaired quality of life, but also with increased morbidity and mortality (84–86). Sleep loss alters carbohydrate metabolism and endocrine function, and has been associated with incident diabetes (87,88). Additionally, falls constitute the greatest risk factor for fractures among the elderly (89). Nocturia is associated with an increased risk for both falls and fractures (90–96). Increased risk for mortality has been reported not only in the elderly, but also among younger men and women (33,93,97,98). In a Japanese study among the elderly, at least 2 voids per night was associated with a doubled risk for fractures and mortality (96).

Results of a US study among older men and women show a more modest association of nocturia (defined as ≥3 voids/night) with increased risk for falls (95). Data from the Third National Health and Nutrition Examination Survey (NHANES III) showed nocturia (≥2 voids/night) was associated with increased mortality risk in younger men and women (<65 years) rather than in the elderly, and among those without comorbid conditions (heart disease, diabetes) (33). Data from the Krimpen study among older men (55–84 years of age) showed no association of nocturia with increased mortal-ity risk after accounting for confounding factors (99). In contrast, results of the Olmsted County Study in men 60 years and older showed an almost 50% increase in mortality risk after multivariate analyses (100). Increased mortality risk with nocturia among the elderly may be due to increased

risk for falls and fractures associated with nighttime voiding episodes. Alternatively, nocturia may be an indicator of frailty. Increased risk for morbidity and mortality among younger age groups and among those without prevalent comorbid conditions may indicate nocturia as a marker for impend-ing morbidity (e.g. cardiovascular disease or diabetes), as an association of nocturia with chronic illnesses has been reported (101,102).

Although no research articles have been published on economic impact of nocturia, a few studies have investigated the impact of nocturia and associated sleep loss on work productivity. Nocturia has been associated with daytime fatigue and reduced vitality (19,69). A study of 203 working adults in Sweden has shown reduced work productivity with nocturia. Compared with age- and gender-matched controls, those with ≥1 voids per night had significant work productivity and activity impairment, impairment in non-work activities, and reduced vitality and quality of life (103).

3.4.5 Conclusions

Nocturia is one of the most common LUTS, with similar overall prevalence in both genders.

The prevalence of nocturia is higher among young women than young men, but the prevalence increases more markedly with age in men.

The literature on the incidence of nocturia remains relatively sparse. Incidence of nocturia increases with age, but significant short-term fluctuation in nocturia severity in individuals makes studies on incidence challenging.

Two or more episodes of nocturia per night constitutes clinically meaningful nocturia severity in the general population, affecting quality of life and perceived health, while a single episode usually does not.

Nocturia has been suggested to increase risk for falls, fractures, death, and impaired productivity.

3.4.6 Recommendations

Epidemiological studies need to employ strictly defined and clearly stated criteria of terminology and assessment.

Approaches to identify intra-individual variation and other confounding influences need to be considered.

Longitudinal studies using high-quality methodology remain a priority requirement.

Nocturia of twice or more per night may be a threshold of clinical significance in the general population. However, this threshold is not irrefutably established, and should not be extracted to sub-populations. Research into all grades of nocturia severity may yield information of clinical relevance.

3.5 Pathophysiology

Our knowledge of the pathophysiology of nocturia has really not changed over the last decade.

What has changed is the knowledge that nocturia has multi-factorial etiology, which is not always urological in origin.

In normal adult urinary physiology, the amount of urine made at night is less than the functional bladder capacity during the daytime, and hence adults void more during the daytime and can sleep at night without having to wake up to void. This underpins the Ni, calculated as nocturnal urine volume divided by maximum voided volume (MVV; functional bladder capacity). It is positive if greater than 1. The normal pattern of voiding is established early in childhood and should, in theory, be maintained throughout adult life, and is based on the arginine vasopressin (AVP) control mech-anism (104). Therefore, urine production and storage at night is based on two simple physiological events: the first is that the person needs to go to sleep and the second is that urine needs to be produced and stored in the bladder. If, for whatever reason, one or both of these two mechanisms are disturbed, then nocturia will result. Hence, by understanding this basic principle, it is possible to predict the pathophysiology of nocturia, which can be divided into two broad groups of non-patho-logical or pathonon-patho-logical nocturia.

Non-pathological nocturia essentially means waking up for a reason other than the need to pass urine and feeling the desire to pass urine once awake (105), resulting in a “convenience” void (106). This may be due to, for example, noises outside the house, partner snoring, baby crying, light in the room being switched on, etc. Therefore, by definition, these are external factors and non-pathological.

Pathological nocturia, on the other hand, results from medical factors affecting either the sleep pattern, or production and storage of urine. It can be divided into five broad categories (107):

1. Reduced voided volume (indicating a reduced capacity of the bladder to store urine) throughout the 24-hour period, or exclusively during the hours of sleep (low nocturnal blad-der capacity). This may be due to a variety of urological conditions, such as infravesical outflow obstruction, radiation cystitis, over-active bladder (OAB) syndrome, bladder calculi, or other primary bladder pathology causing a reduction in the anatomical capac-ity. Alternatively, the reduction in capacity may result from extrinsic compression by pelvic masses or urogenital prolapse (108).

2. 24-Hour (global) polyuria, characterized by excessive urine production during both day and night (indicating polyuria where 24-hour urine volume exceeds 40 mL/kg). This may be due to untreated diabetes mellitus (DM), diabetes insipidus (DI; central or nephro-genic), polydipsia (dipsogenic or psychonephro-genic), or hypercalcemia. Drugs including diuretics, selective serotonin reuptake inhibitors (SSRIs), calcium channel blockers, tetracycline, lith-ium, carbonic anhydrase inhibitors work by several diverse mechanisms relevant to noctu-ria, such as increased urine output by way of disturbance of AVP secretion, AVP receptor inhibition, aquaporin level modification, atrial

natriuretic peptide (ANP) increase or action on proximal tubules, effect on the central nervous system, and sleep disturbance (10,108).

3. Excessive urine production rate only at night, in the setting of a normal 24-hour urine output (i.e. NP). The recommendation of the ICS is to define NP as a nocturnal output exceeding 20% of total 24-hour output in the young (aged 21–35 years) and exceeding 33%

of total 24-hour output in the elderly. This is known as the nocturnal polyuria index (NPi).

Other definitions that have been used include nocturnal urine production exceeding 6.4 mL/kg, nocturnal urine output >0.9 mL/min, or nocturnal urine production >90 mL/hr of urine produced during sleep (108,109,110).

It should be noted, however, that no studies assess the validity of these cut-off points in clinical practice. Nocturnal polyuria may be a result of peripheral edema and ANP secretion secondary to congestive heart fail-ure, autonomic neuropathy, venous stasis, lymphostasis, hepatic failure, hypoalbumin-emia/malnutrition, or nephrotic syndrome.

It may also be caused by excessive evening fluid intake; nighttime drinking; circadian

defect in the secretion of AVP (including central nervous system lesions of the hypo-thalamic-pituitary axis, Parkinson’s disease, multiple sclerosis); drugs including diuretics, ethanol, and steroids; renal tubular dysfunc-tion (including DM and albuminuria); and obstructive sleep apnea (OSA) (111).

4. Sleep disorders–including primary (insom-nia, periodic leg movements, narcolepsy, arousal disorders such as sleepwalking and nightmares) and secondary (cardiac failure, chronic obstructive pulmonary disease (COPD), endocrine disorders)–can cause nocturia. Neurological conditions (Parkinson’s disease, dementia, epilepsy);

psychiatric conditions (depression, anxiety);

chronic pain disorders; alcohol or drug use (consumption or withdrawal); and medica-tions (corticosteroids, diuretics, βadrenergic antagonists, thyroid hormones, psychotro-pics, anti-epileptics) have all been implicated in causing nocturia (81,83,112).

5. Combinations of the above, resulting in mixed etiology requiring a multi-disciplinary approach to diagnosis and treatment.

3.5.1 Risk factors