Lower Urinary Tract
The impact of sleep apnoea syndrome on nocturia according to age in men
In-Young Yoon, Department of Neuropsychiatry, Seoul National University Bundang Hospital 300 Gumi-dong, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-101, Korea. e-mail: email@example.com
Study Type – Symptom prevalence (cohort)
Level of Evidence 2b
What's known on the subject? and What does the study add?
Sleep apnoea syndrome (SAS) can be a risk factor for nocturia, although whether the relationship between nocturia and SAS changes according to age remains to be addressed.
SAS has a modest impact on nocturia frequency and the prevalence of pathological nocturia in young adults and middle-aged men. However, SAS may not be a risk factor for nocturia in the elderly, and age-related urinary diseases and voiding dysfunctions could over-ride the influence of SAS on nocturia in the elderly.
- • To assess the association between nocturia and sleep apnoea syndrome (SAS) according to age, as well as to determine the factors related to nocturia.
PATIENTS AND METHODS
- • A total of 1757 men who had been referred to a sleep laboratory underwent polysomnography.
- • Nocturia frequency was assessed using a questionnaire, and pathological nocturia was defined as the need to void two or more times per night.
- • The Pittsburgh Sleep Quality Index (PSQI) and Beck Depression Inventory (BDI) were applied to all study subjects.
- • Nocturia frequency was significantly correlated with age (r= 0.405, P < 0.001) and the apnoea–hypopnoea index (AHI) (r= 0.065, P < 0.01).
- • In those men aged <65 years, significant correlations were found between nocturic frequency and age, AHI, BDI and PSQI.
- • Multiple regression analysis showed that age (β= 0.303, P < 0.001), AHI (β= 0.107 P < 0.001) and benign prostatic hypertrophy (BPH; β= 0.069, P < 0.01) were associated with nocturia, and that the presence of pathological nocturia was predicted by BPH (odds ratio [OR], 2.77; P < 0.01), age (OR, 1.09; P < 0.001) and AHI (OR, 1.02; P < 0.001).
- • However, in men aged >65 years, nocturia frequency was significantly associated with BDI and PSQI, although no relationship was found between nocturia frequency and SAS parameters.
- • BPH was more frequently observed in elderly men with pathological nocturia than in those without pathological nocturia (OR, 2.18; P < 0.05).
- • In the elderly, SAS may not be a risk factor for nocturia.
- • Age-related urinary diseases and voiding dysfunction may over-ride the influence of SAS.
atrial natriuretic peptide
Beck Depression Inventory
Pittsburgh Sleep Quality Index
sleep apnoea syndrome.
Sleep apnoea syndrome (SAS) is characterized by nocturnal hypoxaemia and frequent arousal during sleep as a result of repetitive nocturnal respiratory pauses . In addition to the frequently reported complications of SAS, such as daytime sleepiness, cardiovascular disease and cognitive dysfunction, several studies suggest that nocturia may be related to SAS [2–4]. Oztura et al.  found that SAS was significantly associated with nocturnal urination in 1970 patients with SAS. In 65 ischaemic stroke patients, Chen et al.  found that patients with severe obstructive sleep apnoea were older, and also had a significantly higher desaturation index and nocturia frequency than those without.
Although the mechanism by which SAS develops nocturia has not been determined, hypoxaemia, a negative intrathoracic pressure and the release of peptides, such as vasodilators or aldosterone inhibitors, are considered to increase urine output during sleep . In addition, other medical conditions, such as cardiovascular or endocrine diseases, age-related brain diseases, and lower urinary tract disorders and medication, could result in nocturia [8,9]. Because these conditions are frequently observed in the elderly and (similar to SAS) can impact on nocturia, we considered that the relationship between nocturia and SAS may change with age.
Relatively few studies have addressed the effect of age on the relationship between nocturia and SAS. In one study of 138 SAS patients, Hajduk et al.  suggested that symptoms of sleep apnoea are more associated with pathological nocturia in young rather than older men. In another study of nocturia conducted in 73 subjects, Moriyama et al.  found that SAS was modestly related to nocturia in subjects aged ≤50 years, although not in those aged >50 years . However, these studies each had limitations to consider. No clear age definition of ‘young’ and ‘old’ was provided by Hajduk et al. , whereas Moriyama et al.  dichotomized subjects to those aged ≤50 years and >50 years, which is an unusual choice in studies on ageing. In addition, both studies suffered from small sample sizes and, because the impact of SAS on nocturia is probably subtle, larger-scale studies are required to explore the relationship between SAS and nocturia [5,10,11]. Accordingly, the present study aimed to investigate the association between SAS and nocturia in men aged ≤65 years and >65 years, as well as to identify the factors related to nocturia in each age group.
PATIENTS AND METHODS
In the present study, 1757 men were enrolled who were referred to the sleep laboratory at Seoul National University Bundang Hospital from July 2005 to April 2011 for evaluation of suspected sleep disturbance. The study inclusion criteria comprised men aged >30 years with or without well-controlled BPH, hypertension (HTN), diabetes mellitus (DM) or cardiovascular disease (CVD). If men were taking medication for BPH, DM or HTN, they were classified as medication-positive. Candidates with uncontrolled HTN or DM were excluded. The 1757 men were divided into two groups: a young and middle-aged group (aged 30–64 years; n= 1517) and an elderly group (aged 65–84 years; n= 240). All of the men underwent a clinical examination, psychiatric evaluation and nocturnal polysomnography (NPSG). The Pittsburgh Sleep Quality Index (PSQI) was used to evaluate subjective sleep complaints, the Epworth Sleepiness Scale to assess daytime sleepiness, and the Beck Depression Inventory (BDI) to evaluate mood symptoms. Nocturia was defined as self-reported awakening at night to urinate, and pathological nocturia was defined as awakening at least twice per night to urinate . The study protocol was approved by the Institutional Review Board of Seoul National University Bundang Hospital.
For NPSG, an Embla™ N7000 (Embla, Reykjavik, Iceland) was used with standard electrodes and sensors. Electroencephalography electrodes were applied at C3/A2, O1/A2 and O2/A1, and two electrooculography electrodes were applied at the sides of both eyes to record horizontal and vertical eye movements. Submental electromyography electrodes were applied at the submentalis muscle, and electromyograms at both anterior tibialis muscles recorded limb movements during sleep. Strain gauges were used to record chest and abdominal respiratory movements, and nasal pressure cannulas were used to record airflow. Arterial oxygen saturation was measured using a pulse oximeter applied on an index finger. Based on the criteria of Rechtschaffen and Kales , we scored every 30-s epoch of NPSG. Apnoea was defined as the complete cessation of airflow for at least 10 s, and hypopnoea was defined as a substantial reduction in airflow (>50%) for at least 10 s or a moderate reduction in airflow for at least 10 s associated with EEG arousal or oxygen desaturation (≥4%) . AHI was defined as the total number of apnoeas and hypopnoeas per hour of sleep, and the oxygen desaturation index was defined as the number of oxygen desaturations (≥4%) per hour of sleep. The severity of SAS was classified as mild (AHI ≥5 and <15), moderate (AHI ≥15 and <30) or severe (AHI ≥30) . The three groups compared in the present study were: (i) normal controls (AHI <5); (ii) men with a mild to moderate degree of SAS (AHI ≥5 and AHI <30); and (iii) men with a severe degree of SAS (AHI ≥30).
Pearson's correlation coefficients were calculated to determine relationships between nocturnal urination frequency and NPSG or demographic variables. The three groups classified according to the severity of AHI were compared with respect to nocturnal urination frequency, and demographic, clinical and NPSG variables. A chi-squared test was used to analyze categorical data and anova was used for continuous data. Regression analysis was used to identify independent predictors of nocturic frequency and pathological nocturia. Analyses were performed using SPSS, version 18.0 (SPSS, Chicago, IL, USA). P < 0.05 was considered statistically significant.
CORRELATIONS BETWEEN NOCTURNAL URINATION FREQUENCY AND DEMOGRAPHIC CHARACTERISTICS OR POLYSOMNOGRAPHIC FINDINGS
The mean (sd, range) age of the 1755 men taking part in the present study was 50.1 (11.4, 30–84) years, mean (sd, range) AHI was 27.7 (22.6, 0–103.9) and mean (sd, range) lowest oxygen saturation was 81.8 (8.49%, 50–96.6%). Significant correlations were found between nocturnal urination frequency and age (r= 0.405, P < 0.001), AHI (r= 0.065, P= 0.007), BDI (r= 0.226, P < 0.001) and PSQI (r= 0.281, P < 0.001). Among younger and middle-aged men, nocturnal urination frequency also showed significant correlations with age (r= 0.313, P < 0.001), AHI (r= 0.093, P < 0.001), BDI (r= 0.200, P < 0.001) and PSQI (r= 0.278, P < 0.001). However, in elderly men, nocturnal urination frequency was only significantly related to BDI (r= 0.166, P= 0.010) and PSQI (r= 0.136, P= 0.035). No association was found between nocturic frequency and SAS parameters (Table 1).
Table 1. Correlation between nocturia frequency and age, apnoea-hypopnoea index (AHI), Pittsburgh Sleep Quality Index (PSQI) and Beck Depression Inventory (BDI)
Comparisons of SAS patients and normal controls with respect to nocturnal urination, demographic characteristics and NPSG findings.
Table 2 shows comparisons of the three groups with respect to nocturia, demographic characteristics and NPGS findings in young and middle-aged men. Age (F= 4.98, P= 0.007), body mass index (F= 84.08, P < 0.001), HTN (P < 0.001) and DM (P= 0.037) were found to be significantly different in the three groups. Mean nocturia frequency was also significantly different among the three groups by analysis of covariance with age, BDI, PSQI, HTN, DM and medication as covariates (P < 0.001). Men with severe SAS had a higher nocturia frequency than men without SAS or with mild to moderate SAS, although no difference was observed between the two latter groups. The prevalence of pathological nocturia was significantly different in the three groups by the chi-squared test (P= 0.002). In the elderly, AHI (F= 354.59, P < 0.001), lowest oxygen saturation (F= 44.73, P < 0.001), body mass index (F= 7.08, P= 0.001) and PSQI (F= 3.05, P= 0.049) were significantly different in the three groups, whereas mean nocturia frequency and the prevalence of pathological nocturia were not different (Table 3).
Table 2. Comparison of patients with sleep apnoea syndrome (SAS) and normal controls with respect to nocturia frequency, demographic characteristics and nocturnal polysomnography findings in men aged <65 years
|BPH, n (%)||5 (2.3)||19 (2.6)||11 (1.9)||0.734|
|HTN, n (%)||21 (9.8)||154 (21.0)||167 (29.3)||<0.001|
|DM, n (%)||7 (3.3)||41 (5.6)||45 (7.9)||0.037|
|CVD, n (%)||2 (0.9)||11 (1.5)||8 (1.4)||0.819|
|Medication, n (%)||12 (5.6)||94 (12.8)||95 (16.7)||<0.001|
|Frequency of nocturia†||0.79||0.80||0.94||<0.001|
|Pathological nocturia, n (%)||20 (9.3)||76 (10.4)||92 (16.2)||0.002|
Table 3. Comparison of patients with SAS and normal controls with respect to nocturia frequency, demographic characteristics and nocturnal polysomnography findings in men aged ≥65 years
|BPH, n (%)||6 (26.1)||26 (19.8)||9 (10.5)||0.096|
|HTN, n (%)||9 (39.1)||55 (42.0)||45 (52.3)||0.266|
|DM, n (%)||5 (21.7)||18 (13.7)||13 (15.1)||0.612|
|CVD, n (%)||0 (0)||10 (7.6)||9 (10.5)||0.252|
|Medication, n (%)||3 (13.0)||34 (26.0)||20 (23.3)||0.403|
|Frequency of Nocturia||1.8||1.7||1.8||0.815|
|Pathological nocturia, n (%)||10 (43.5)||57 (43.5)||41 (47.7)||0.831|
PREDICTORS OF NOCTURIA
Multiple regression analysis on nocturia frequency and logistic regression analysis on pathological nocturia were performed in young and middle-aged men. The variables analyzed as predictors for nocturia were: age, AHI, BDI, BPH, HTN, DM and CVD. Age (β= 0.303, P < 0.001), AHI (β= 0.107, P < 0.001) and BPH (β= 0.069, P= 0.005) were found to be associated with nocturia frequency, and BPH (OR, 2.77; 95% CI, 1.33–5.76), age (OR, 1.09; 95% CI, 1.07–1.11) and AHI (OR, 1.02; 95% CI, 1.01–1.02) were found to predict the presence of pathological nocturia (Table 4). In elderly men, the clinical and polysomnographic characteristics of subjects with or without pathological nocturia were compared. BPH was more frequently observed in elderly men with pathological nocturia than in those without (OR, 2.18; 95% CI, 1.10–4.34) (Table 5).
Table 4. Independent predictors of nocturic frequency and pathological nocturia in men aged <65 years old (n= 1517)
Table 5. Comparison of demographic characteristics and nocturnal polysomnography findings in men aged ≥65 years with or without nocturia
|BPH, n (%)*||25 (23.1)||16 (12.1)||0.024|
|HTN, n (%)||43 (39.8)||66 (50.0)||0.115|
|DM, n (%)||13 (12.0)||23 (17.4)||0.245|
|CVD, n (%)||10 (9.3)||9 (6.8)||0.486|
|Medication, n (%)||23 (21.3)||34 (25.8)||0.419|
In the present study, a significant, although modest, relationship was observed between SAS and nocturia in young and middle-aged men, although no such association was found in elderly men. The mechanisms by which SAS induces nocturia have not been elucidated, although several putative mechanisms involving atrial natriuretic peptide (ANP) have been proposed [7,16]. First, an obstructive airway produces negative intrathoracic pressure as a result of continuous respiratory effort, which stimulates venous return to the right atrium. ANP is then released by atrial myocytes in response to right atrial distension [3,17]. Second, right ventricular enlargement resulting from right atrial distension promotes a leftward shift of the interventricular septum, impairing left ventricle filling and reducing stroke volume . Consequently, the heart perceives a false fluid overload signal and secrets ANP in the atria . Third, hypoxia and hypercapnia resulting from apnoea stimulate the sympathetic nervous system, which leads to vasoconstriction, BP elevation and an increase in left ventricle afterload , which reduces cardiac output and triggers a false fluid overload signal, as well as ANP secretion . Based on the above mechanisms, the resultant ANP release in SAS could increase nocturnal urine output in SAS patients . ANP promotes urination by inhibiting the secretion of aldosterone and arginine vasopressin, as well as by increasing glomerular filtration [16,21,22].
There was no association between nocturia and SAS in the elderly in the present study. These findings are similar to those reported by Hajduk et al. , who found that sleep apnoea symptoms were associated with pathological nocturia in young men more so than in older men. In addition, the results obtained in the present study are partially supported by those reported by Moriyama et al. , who observed that, in men aged ≤50 years, obstructive sleep apnoea was significantly related with nocturia but, in men aged >50 years, AHI did not differ significantly in men with and without nocturia. On the other hand, several other studies have produced contradictory results. Umlauf et al.  reported higher night-time urine output, plasma ANP and urine ANP excretion in nine subjects with higher AHI levels among thirty community dwelling older men and women. However, night-time urine output volume differed from nocturia, which is usually defined as the need to wake up one or more times per night to void . Endeshaw et al.  also found higher frequencies of nocturnal urination among community-dwelling older adults with severe SAS. However, although the severe SAS group in the study by Endeshaw et al.  had a significantly higher nocturia frequency than the mild to moderate SAS group, no significant difference was observed between the severe and no SAS groups. In addition, no significant correlation was found between AHI and nocturia by Spearman correlational analysis. Thus, although SAS should be sought in elderly men who are found to have nocturnal polyuria unrelated to cardiac dysfunction or peripheral oedema, it is postulated that SAS, as a whole, has minimal impact on nocturia in the elderly.
Nocturia in the elderly may be associated with factors that are more common in the elderly or can occur secondary to pathological conditions, including SAS, although usually it is considered to be caused by age-related structural changes in the urinary system. These changes include a decreased functional bladder capacity, a decreased ability to postpone urination and an increase in post-voiding residual urine volumes [24,25]. In one study conducted in 2081 community-dwelling elderly subjects (>65 years), it was reported that increased nocturia frequency in the elderly was not closely correlated with HTN, DM, the use of diuretics, or medication for DM and HTN . In line with these studies, we were unable to find any relationship between nocturia and concomitant diseases, including SAS, HTN, DM or cardiovascular diseases, although BPH was more frequently observed in subjects with pathological nocturia than in those without. In a Chinese study, BPH was found to induce nocturia by decreasing nocturnal bladder capacity with advancing age .
In the present study, a significant correlation was found between nocturia frequency and BDI and PSQI in all men, regardless of age. Several other studies have reported similar results. In one study conducted in 547 men, nocturia was found to be significantly associated with depressive symptoms, and it was suggested that nocturia may be predictive of depression . Another study reported a significant correlation between the severity of nocturia and poor sleep quality, and found that sleep quality was improved after surgical intervention . Although a close association exists between depressive symptoms, poor sleep quality and nocturia, no causal relationship has been established. Nocturia in itself can cause depression because patients with nocturia frequently experience sleep fragmentation, inducing depressive symptoms  but, on the other hand, patients with depression frequently wake at night and this could trigger the need to urinate.
The present study has several limitations that warrant consideration. First, urinary frequencies were obtained by subject recall, and thus may be inaccurate. However, there are few feasible objective ways of assessing nocturia in large populations. Second, the representativeness of the study subjects is in doubt because they were recruited from among patients who sought treatment in a sleep clinic, and thus a high prevalence of SAS was expected. Third, we excluded women, and thus, our results are limited to a population of men. Additional prospective studies are needed to identify the causative factors for nocturia. Nevertheless, the present study has meaning because it explored the effect of age on the relationship between SAS and nocturia. SAS was found to have a modest impact on nocturia frequency and the prevalence of pathological nocturia in young adults and middle-aged men after controlling for age, AHI, BPH, HTN, CVD and medication. However, SAS may not be a risk factor for nocturia in the elderly. It is also possible that age-related urinary diseases and voiding dysfunctions over-ride the influence of SAS on nocturia in the elderly.
This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (grant number 2010-0008886).
CONFLICT OF INTEREST