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Corresponding author. Clinical Research and Trials Unit, Norfolk and Norwich University Hospital, Colney Lane, Norwich, NR4 7UY, United Kingdom. Tel. +44 1603286611.
Sleep is a vital element in a human's general health. However, sleep may lose its “healing” function, especially through ageing. Sleep in the elderly is characterised by less restorative sleep and more frequent awakenings. One of the main causes of sleep impairment in this population, besides ageing, is nocturia. The aetiology of nocturia includes several factors, among others somatic diseases, age-related endocrine alterations, bladder outlet obstruction, and detrusor overactivity (often associated with benign prostatic hyperplasia) and sleep apnoea. Because most of these factors are often prevalent in the elderly, nocturia is often considered as a normal consequence of ageing. However, lack of sleep due to the frequent nocturnal awakenings may have deleterious effects on general health status. Indeed, data not only from nocturia, but also from many pain or pruritus-associated diseases, clearly demonstrate that disturbance of the normal sleep pattern results in poor quality of sleep, which, in turn, leads to poor quality of life. Frequent nocturnal awakenings may induce diminished vitality, increased susceptibility for diseases, impaired cognitive performance and alertness, depression, and even a higher mortality. Moreover, patients who have nocturia have an increased risk for accidents, falls, and fractures, especially the elderly, who often already have impaired motor and cognitive functioning. Hence, nocturia should not be seen as just another age-related problem but, considering the substantial impact it can have on the quality of sleep and quality of life, it should be recognised as a condition that needs to be taken seriously and treated appropriately.
Nocturia or nocturnal micturition is a widespread phenomenon, especially in the elderly. Given the high prevalence of nocturia in this population, it is often considered as a usual part of ageing with one nocturnal void being within normal limits. However, two or more nocturnal voids are regarded as bothersome by the patient and usually result from one or more underlying pathophysiologic conditions [
Three major conditions inducing nocturia are polyuria (eg, due to excessive fluid intake or diabetes), nocturnal polyuria (eg, due to right-sided congestive heart failure or hypoalbuminemia), and reduced bladder capacity (eg, due to cancer or fibrosis). Reduced bladder capacity, however, is also frequently the result of detrusor overactivity or bladder outlet obstruction (BOO) in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) [
As a result, it has become apparent over the past few years that nocturia is not only a urologic problem, but that it also negatively influences the patient's quality of life (QoL) [
Subjective sleep characteristics of 1,485 males and females aged 50–93: effects of sex and age, and factors related to self-evaluated quality of sleep.
]. The frequent nocturnal awakenings associated with nocturia lead to a poor quality of sleep (QoS) due to structural disturbances of the normal sleep architecture [
]. In addition, a disturbed sleep pattern can also be observed in people with chronic pain, pruritus, or depression and these conditions may also increase the nighttime voiding frequency [
Sleep disorders as a result of nocturia or any other of these conditions have a substantial negative impact on an individual's QoL. Indeed, an increased severity of nocturia is positively correlated with a poorer overall health status [
]. Besides an increase in daytime fatigue and impaired performance, sleep disruption may also have more serious consequences such as immunosuppression, depression, endocrine and metabolic alterations, an increased incidence of falls, fractures, and sleep-related accidents on the road and at work, and even a higher mortality rate [
Given the pivotal role of sleep disruption, caused by nocturia, ageing, or another disorder in the deterioration of the patient's QoL, this paper aspires to provide an overview of the aetiology of nocturia and how this, together with ageing, affects the normal sleep pattern and the therewith associated QoS. How QoS influences QoL and how other disorders that impair sleep may have an effect on QoL are also discussed.
2. The multifactorial aetiology of nocturia
Nocturia is usually caused by underlying pathophysiologic disorders, which may be present separately or in combination. These include diurnal and nocturnal overproduction of urine (polyuria), nocturnal overproduction of urine (nocturnal polyuria), or a reduced bladder capacity [
]. Nocturia, however, may also result from a wide range of conditions giving rise to sleep disturbance such as depression or insomnia or those involving pain or pruritus [
]. However, in these conditions, nocturia is rather a secondary problem due to nighttime awakening, which is often accompanied with nocturnal voiding or nighttime drinking.
2.1 Polyuria
According to the International Continence Society (ICS), polyuria is defined as the measured production of more than 2.8 l of urine in 24 h in a 70-kg adult [
The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society.
] and is associated with a daytime and nighttime overproduction of urine. Although habitual excess fluid intake is regarded as the most common cause of polyuria, increase in total urine production may also result from disease. Diabetes mellitus (DM) as well as the more rare condition diabetes insipidus (DI) both give rise to disease-associated polyuria. DM is characterised by glucose-induced osmotic diuresis leading to the increase of urine flow rate and acceleration of body fluid turnover. In addition, plasma levels of the antidiuretic hormone arginine vasopressin (AVP) are elevated in patients with DM, probably as a countermeasure for the increased diuresis. These chronically elevated AVP levels, however, may become harmful for the kidney and ultimately lead to diabetic nephropathy [
]. DI, on the other hand, is characterised by the excretion of abundant volumes of dilute urine and can be triggered by two fundamentally different effects: inadequate or impaired secretion of AVP from the posterior pituitary gland (central or neurogenic DI) or impaired or insufficient renal response to AVP (nephrogenic DI) [
Nocturnal polyuria is defined as an increase in nighttime urine production with a corresponding decrease in daytime urine output, resulting in an overall normal 24-h urine volume. Because the normal range of nocturnal urine production differs with age, nocturnal polyuria is defined to be present when >20% (in young adults) to 33% (in individuals aged >65 yr) of the 24-h urine output occurs during the 8 h while the patient is in bed [
The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society.
]. It is proposed that primary or idiopathic nocturnal polyuria is caused by disruption of the normal AVP levels. An increase of the diurnal AVP secretion results in a lower volume of concentrated urine during daytime, whereas a disruption in the normally increased nighttime AVP secretion gives rise to large quantities of dilute urine [
]. These alterations in AVP secretion originate from changes in the hypothalamic-pituitary axis due to stroke, but more often as a result of ageing. Indeed, like other circadian rhythms, the 24-h circadian rhythm of AVP plasma levels tends to be lost in ageing persons. Especially in men with nocturia, the increased nocturnal voiding frequency can be ascribed to a severe decrease or even complete absence in plasma AVP levels during the night [
]. Besides the importance of fluctuations in AVP levels, other age-related effects may lead to an increase in nocturnal voiding. These include a decreased secretion of renin, angiotensin II, and aldosterone, an increase in atrial natriuretic peptide (ANP) secretion, and diminished sodium conservation and renal concentration capacity [
In addition, several secondary causes can form the basis of nocturnal polyuria. An important causative effect is fluid accumulation in the lower extremities due to venous stasis, hypoalbuminemia, or right-sided congestive heart failure (CHF). The elevation of the extracellular fluid volume in the latter of these conditions is associated with atrial stretch. This, in turn, triggers the release of ANP resulting in increased diuresis and natriuresis [
]. Additionally, obstructive sleep apnoea (OSA) is thought to mimic the process of atrial stretching observed in CHF resulting from the negative thoracic pressure induced by the continuous respiratory effort posed against a closed airway [
]. A primary cause may be found in a decreased structural bladder capacity. Although this can be brought about by disease-related factors such as cancer in situ, fibrosis, or radiation therapy [
], ageing also contributes to a decrease in bladder capacity. Ageing is associated with an increase in the collagen-to-smooth muscle ratio in the bladder, which results in an increased stiffness of the bladder with corresponding diminution of its structural capacity [
]. Furthermore, age-related changes may also contribute to the high prevalence of overactive bladder in the elderly population, which is accompanied with an increase in daytime and nocturnal voiding frequency. Neurochemical studies using human detrusor strips indicate that purinergic transmission increases with age, which contributes to overactive bladder [
]. Besides age, underlying pathologic factors such as central nervous system diseases or urinary tract infections may also give rise to overactive bladder [
A major cause of nocturia in elderly men, however, is LUTS/BPH. An enlarged prostate associated with BPH gives rise to BOO and this is believed to contribute to both signs and symptoms of disease severity, especially through alterations in bladder function with an impact on its storage capacity [
]. The pathophysiology associated with BOO is a significant increase in bladder weight, neoangiogenesis, and reduced blood flow to the muscle fibres of the detrusor. During this initial compensation phase, 80% of the bladder contractile function is maintained ensuring a complete emptying of the bladder. During the second phase, however, a further decompensation of the detrusor occurs, with progressive bladder hypertrophy and reduction in bladder function and compliance (Fig. 1). The alterations in detrusor activity, the poor compliance, and the failure of the bladder to compensate for BOO, therefore, ultimately result in bladder storage symptoms (urgency and frequency) and voiding symptoms (diminished flow and incomplete emptying) [
Fig. 1Impact of benign prostatic hyperplasia (BPH) on bladder physiology and function. BPH is frequently associated with bladder outlet obstruction (BOO), which gives rise to an increase in bladder weight, neoangiogenesis, and progressive detrusor decompensation and a decrease in bladder function and compliance.
Using animal models, it was demonstrated that these progressive bladder alterations can be, though incompletely, reversed after removal of the obstruction [
Morphological, stereological, and biochemical analysis of the mini-pig urinary bladder after chronic outflow obstruction and after recovery from obstruction.
]. Because no consensus has been reached regarding “the point of no return” beyond which bladder function will not recover after the removal of BOO associated with BPH [
] and long-term consequences of BOO on bladder function may stay present after surgery, BPH remains to be considered as an important trigger for nocturia.
3. Normal sleep pattern is affected by age
3.1 Normal sleep pattern
To understand the implications of nocturia on QoS and associated QoL of a patient with LUTS/BPH, it is initially imperative to gain more insights into the normal physiology of sleep and its importance for human functioning.
Sleep is an essential part of life because it contributes significantly to the restoration and recuperation of our physical and mental functioning. Up to the first half of the 20th century, sleep was considered to be a passive state of unconsciousness. However, it has become clear that it is rather a highly dynamic brain process driven by the interaction of two essentially independent mechanisms: the homeostatic drive to sleep and the circadian rhythm [
Sleep is characterised by the combined recording of signals from the electroencephalogram, the electrooculogram, and the electromyogram. The resulting polysomnogram identifies five different, well-defined stages. Stages 1 to 4 represent the stages with increasing sleep depth after falling asleep, also known as the non–rapid-eye-movement or nREM sleep. Stages 3 and 4 are often grouped together and are referred to as deep sleep or slow wave sleep (SWS; Fig. 2). Metabolism falls with increasing sleep stages and SWS is characterised by slow breathing, low heart rate, and low cerebral blood flow and represents the deepest sleep. Although it comprises only 25% of our total sleep time, SWS is regarded as the most important part of the night because it is considered to represent the daily process of recuperation. However, it is also accompanied with the highest arousal threshold. The initial four stages of nREM sleep are followed by REM sleep, which is typically characterised by a state of high brain activity and a metabolic rate that is increased above resting waking levels [
Fig. 2Schematic representation of the cycling of the human sleep stages at early adulthood (A) and old age (B). A normal sleep pattern consists of different non–rapid-eye-movement (nREM) stages (1–4), which are followed by REM sleep. During the night there is an increase in REM sleep with a corresponding decrease in stage 4 sleep. The sleep pattern of elderly is further characterised by a decrease in stage 4 sleep and an increase in REM sleep and the amount of nocturnal awakenings.
In a normal adult, the progression of sleep during the nighttime is characterised by four to six repetitive but slightly changing sleep cycles of 90–120 min consisting of an alternation between nREM and REM sleep (Fig. 2) [
]. Although considerable variation exists among individuals, sleep in a normal adult generally lasts approximately 8 h. The first part of the night is predominated by deep sleep stages 3 and 4, whereas the amount of REM sleep increases during the last part (Fig. 2). Hence, the proportion of deep, recuperative SWS decreases with each cycle [
]. Provoked awakening during SWS interferes significantly with the normal sleep pattern and gives rise to decreased daytime energy and performance. Therefore, to ensure objective and subjective QoS and daytime functioning, it seems imperative that interruption of sleep during the first part of the night should be avoided as much as possible [
Because patients with LUTS/BPH are in general elderly men, it is also important to consider the effects of ageing on the normal sleep pattern. Sleep is highly age-dependent and sleep characteristics have been shown to change profoundly in the elderly [
]. The REM sleep percentage (of total sleep time) declines dramatically with age: from 50% at birth to 20–25% at adolescence, after which it stabilises. SWS or deep sleep, on the other hand, begins to decrease after adolescence and continues to decrease with increasing age, sometimes disappearing completely in elderly individuals [
Increasing age is also associated with an augmentation in awakening frequency (Fig. 2). Although nighttime awakening is a characteristic of all ages, the elderly find it more difficult to fall asleep again. In addition, the elderly do not preferentially wake during REM sleep as do younger adults, but also during nREM stages (Fig. 2), thereby generating a larger negative impact on daytime functioning [
]. These increased awakenings in the elderly have been attributed to age-related changes in the circadian and homeostatic regulation of sleep. However, the higher tendency of elderly to wake up at night may also result from anatomic and functional insufficiencies, which impair the ability to generate and coordinate stable sleep patterns [
]. As a result of the changes in sleep characteristics and the increased frequency of awakenings during ageing, there is a decline in the overall time of sleep in the elderly [
Overall, it can be stated that the decrease in SWS, the decline in overall sleep time, and the interruption of sleep continuity accounts for the deterioration of the QoS in the elderly leading to an increased propensity for daytime napping and impaired daytime functioning.
4. Insights into the consequences of sleep disturbance: proof from nocturia and other disorders
Sleep disorders are common at all ages, although they are more present in women than in men. Sleep disturbance may originate from primary insomnia (difficulty of sleep initiation or maintenance), secondary insomnia (associated with medical or psychiatric illness such as depression), circadian rhythm disorders (such as jet lag or work shift), sleep-related disorders (OSA), or sleep disruption (sleep fragmentation due to nocturia, pain or pruritus) [
]. A high incidence of arousal and awakenings resulting from either these causes or from increasing age is univocally associated with an impairment of the restorative function of sleep, and by consequence, affects the QoS and the therewith associated QoL.
4.1 Impact of nocturia on QoS and QoL
Although LUTS/BPH has been regarded as a major cause of nocturia in elderly men [
], there is a lack of studies directly investigating the relationship between LUTS/BPH and QoS or QoL. However, accumulating evidence shows that nocturia is associated with sleep disturbance and poor QoS [
Subjective sleep characteristics of 1,485 males and females aged 50–93: effects of sex and age, and factors related to self-evaluated quality of sleep.
To evaluate the impact of nocturia on QoS more thoroughly, the concept of “Hours of Undisturbed Sleep” (HUS) was developed, which is defined as “the time between falling asleep and first awakening to void” [
]. Any disruption of sleep is problematic; however, because of the importance of the restorative function of sleep during the first part of the night (see Section 3.1), HUS should ideally be at least 3–4 h [
]. Sleep impairment not only leads to excessive daytime fatigue, thereby influencing concentration and performance, but may also generate more severe, long-term consequences affecting the general health status [
Frequent sleep interruptions associated with nocturia are likely to interfere considerably with daytime functioning, especially in people who still have an active professional and social life. Indeed, nocturia results in excessive daytime fatigue and lower levels of energy and vitality, and additionally, sleep deprivation leads to confusion and an impaired cognitive performance and alertness [
]. As a consequence, individuals with nocturia do not only have a significantly reduced productivity at work, but they are also confronted with increased confusion and daytime sleepiness at work, which may constitute a major hazard for occupational accidents [
]. Furthermore, sleep impairment gives rise to a high incidence of sleep-related accidents on the road and, especially in the elderly, also to an increase in falls and fractures, which may lead to a considerable increase in health care costs. In addition, these accidents may lead to an early institutionalisation of otherwise healthy elderly people, thereby putting an extra burden on the health care budget [
Emerging evidence also indicates that disturbed sleep brings about alterations in immunologic, endocrine, and metabolic functions. Sleep deprivation affects our host defence system through the diminution of cytokine levels and the amount of natural killer cells [
]. Furthermore, sleep-deprived healthy individuals display a lower glucose tolerance, increased evening cortisol levels, and an increased activity of the sympathetic nervous system with increased levels of catecholamines. These endocrine and metabolic alterations seem to increase the propensity for the development of type 2 DM and cardiovascular diseases [
4.2 Sleep disturbance and its impact on QoL in pain- and pruritus-associated chronic diseases
Sleep disturbance is a prevalent clinical complaint, not only in LUTS/BPH patients with nocturia, but also among persons with acute or chronic pain conditions such as rheumatoid arthritis (RA), irritable bowel syndrome (IBS), and postherpetic neuralgia (PHN) or in those who experience extreme itching (pruritus) [
]. A hallmark of these conditions is that they all have a deleterious effect on the patient's QoL due to their frequently severe symptomatic characteristics. To address the severity of these conditions, one of the physician's standard diagnostic tools is the use of questionnaires that evaluate the patient's QoL, such as the Health Assessment Questionnaire for RA or the IBS-specific QoL questionnaire IBS-QOL. Besides being a diagnostic tool, these questionnaires are also imperative to evaluate the efficacy of therapeutic agents. Together, this indicates the importance of assessing the QoL in these disease areas.
The decrease in the QoL in patients with chronic diseases is not only the result of daytime discomfort, but also results from disease-associated sleep problems. Indeed, disturbed sleep is a key complaint of people experiencing acute or chronic pain. Acute pain during postoperative recovery results in fragmented sleep and reduction of SWS [
]. Furthermore, chronic pain such as lower back pain, headache, or pain associated with chronic diseases such as RA, fibromyalgia, IBS, and PHN have all been shown to affect the normal sleep pattern [
]. In a survey of 242 patients with RA, 60% reported that pain interfered with their sleep. Moreover, fatigue has been positively correlated with disturbed sleep in RA patients [
]. Patients with PHN experience constant or intermittent spontaneous pain, which has been shown to result in sleep disturbance, daytime fatigue, impaired performance, and a profound decrease in QoL [
People diagnosed with IBS, a chronic recurring disorder leading to abdominal pain, display an impaired QoS. In a study by Rotem et al, the sleep pattern and quality of 18 IBS patients was evaluated mainly by polysomnography and actigraphy (activity-based sleep monitoring) and results were compared to those from a control group of 20 matched adults. The results demonstrated that, due to an increase in arousals and awakenings, the cumulative percentage of stage 2 sleep was longer in the IBS group (p < 0.01), whereas recuperative SWS in this group was decreased by more than 70% (p = 0.006; Fig. 3). As a result, IBS patients had significantly more shifts to lighter sleep stages (p < 0.01), reflecting a lighter sleep pattern. Furthermore, the IBS group showed a significant increase in the percentage of awake periods after sleep onset (WASO; p = 0.02; Fig. 3). This decrease in QoS had a significant impact on the daytime functioning. In this respect, the Epworth Sleepiness Scale revealed a significantly higher daytime sleepiness score of 9.0 ± 4.8 in the IBS group compared to 6.4 ± 4.8 in the control group (p = 0.01). In addition, the increased sleep fragmentation impaired QoL as measured by IBS-QOL. Finally, it was shown that patients with more severe IBS had more WASO episodes and lower sleep efficiency (p < 0.04 and p = 0.02, respectively), and, in turn, sleep efficiency was negatively correlated with global disease severity (p < 0.05) [
]. This implies that people with IBS, but also with other chronic diseases that impair sleep, become part of a vicious circle: discomfort and pain prevents people from entering deep stages of recuperative sleep, which, in turn, worsens their symptoms (Fig. 4).
Fig. 3Patients with irritable bowel syndrome (IBS) showed a significant decrease in the percentage of slow wave sleep (SWS; p = 0.006) (A) and a significant increase in the percentage of Wake After Sleep Onset (WASO; p = 0.02) compared to the control group (B)
Fig. 4Vicious circle in which chronic pain leads to nocturnal awakenings that impair the restorative deep slow wave sleep. This not only gives rise to an increased daytime sleepiness and fatigue but also to an increase in severity of pain sensation. QoL = quality of life; SWS = slow wave sleep.
Besides pain-related disorders, extreme manifestations of pruritus, especially originating from a broad range of skin diseases, also give rise to poor QoS and QoL. Patients with moderate to severe allergic dermatosis are subject to enhanced sleep disturbance, which affects their QoL [
]. Furthermore, lichen simplex chronicus, a common pruritic disorder, is associated with an increase in nocturnal awakenings and arousals, especially during nREM sleep stages. This reduces the amount of restorative SWS, and therefore, severely impairs the QoS [
Together, these data clearly indicate that, besides nocturia, many other disorders also induce sleep disturbances, which univocally give rise to a poor QoS, and as a result, further diminish their already poor QoL. Although physicians treating chronic diseases clearly recognise the importance of assessing the QoL during consultations, urologists remain reluctant to introduce this in general practice. However, given the major impact of QoL-associated loss in daytime performance and vitality, urologists should start assessing, measuring, and intervening in disease-induced loss of QoL.
5. Conclusions
Frequent nocturnal awakenings associated with nocturia result in a severe disturbance of the normal sleep pattern. The chronic or acute lack of sleep has a profound negative impact on the overall mental and somatic health status. Daytime fatigue and sleepiness together with a decrease in cognitive functioning and alertness severely impair the daytime vitality and productivity.
Besides nocturia, numerous other conditions may trigger poor sleep including depression, pain, or pruritus. There is a clear association between chronic pain and decreased sleep efficiency, and moreover, this poor QoS in turn gives rise to exacerbation of chronic pain.
Because some chronic diseases are highly prevalent in the elderly, impairment of sleep due to nocturia may not only result in daytime fatigue but may also enhance symptoms associated with comorbid chronic diseases. Improvement of nocturia in these patients will not only result in an increase in QoS, but it may also aid in reducing some symptoms associated with chronic diseases. Hence, future treatment strategies for relief of conditions associated with nocturia should further focus on the improvement of QoS besides QoL.
References
Abrams P.
Nocturia: the major problem in patients with lower urniary tract symptoms suggestive of benign prostatic obstruction (LUTS/BPO).
Subjective sleep characteristics of 1,485 males and females aged 50–93: effects of sex and age, and factors related to self-evaluated quality of sleep.
The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society.
Morphological, stereological, and biochemical analysis of the mini-pig urinary bladder after chronic outflow obstruction and after recovery from obstruction.
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