INTRODUCTION
Nocturia refers to the need to urinate more than once during sleep [1]. Nocturia is more prevalent in women than in men, and the incidence of nocturia increases with age [2]. Nocturia is highly prevalent, and affects up to 60% of elderly people over 70 years of age [3]. Nocturia not only increases the risk of falls or fractures, but also interferes with normal sleep and degrades quality of life [4,5].
The cause of nocturia can be divided into 3 main categories: reduced nocturnal bladder capacity, 24-hour polyuria, and nocturnal polyuria. These three causes can act independently or in combination to induce nocturia [6]. In particular, obstructive sleep apnea (OSA) is a major cause of nocturnal polyuria [7]. The prevalence of OSA is 2%–10% of the population, and OSA is considered an incapacitating chronic disease in which sleep apnea is repeated due to pharyngeal collapse during sleep [8,9]. OSA is considered a common cause of sleep disorders [10].
The association of nocturia with OSA has been reported in a number of studies. Endeshaw et al. [11] reported in a community-based study that sleep-disordered breathing increased nocturia episodes by nearly 100%. Oztura et al. [12] reported that, as the severity of OSA increases, the incidence of nocturia increases. The use of continuous positive airway pressure (CPAP) as a treatment for OSA or the surgical correction of OSA can improve nocturia [13,14].
The association between nocturia and OSA has not been clarified. Therefore, to evaluate the association factors between OSA and nocturia, we compared the results of polysomnography (PSG) according to presence or absence of nocturia in patients with suspected OSA among Korean.
MATERIALS AND METHODS
Patients
This prospective study was conducted from January 2013 to November 2017 at Hanyang University Hospital. A total of 345 patients with sleep apnea who underwent PSG for suspected OSA were enrolled in the study. Exclusion criteria included patients under 19 years of age, patients currently undergoing urology treatment with nocturia, and patients with urinary tract infection. Included patients underwent physical examination, routine laboratory blood test, and urinalysis. In addition, they completed the Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI) questionnaires. The International Prostate Symptom Score and Quality of Life (IPSS/QoL) questionnaire was evaluated to assess voiding symptoms that could affect sleep quality. In the IPSS/QoL questionnaire, nocturia was considered present if the patient recorded >2 on the item 7 question “How many times did you typically get up at night to urinate?” Baseline characteristics, results of PSG, and questionnaire results were compared between patients with nocturia (nocturia group) and patients without nocturia (control group).
Polysomnography
In-lab overnight PSG (Allis 5; Respironics, Murrysville, PA, USA) was performed to diagnose the presence of OSA, as described previously [15]. Briefly, respiratory events were diagnosed as apnea or hypopnea, and the apnea-hypopnea index (AHI) was calculated as the total number of events per hour of sleep. All sleep recordings were scored by a trained sleep technologist according to the recent criteria of the second American Academy of Sleep Medicine manual [16].
Statistical Analysis
In this study, Student t-test was used for continuous variables and chi-square test for categorical variables. The analysis of PSG values according to presence or absence of nocturia was performed through analysis of covariance and logistic regression analysis. Moreover, paired t-test and chi-square test was performed in propensity score matching analysis based on age, hypertension and diabetes mellitus (DM). IBM SPSS ver. 18.0 (IBM Co., Armonk, NY, USA) was used as a statistical analysis program, and P-values<0.05 were considered statistically significant.
Ethics Statement
The study was performed in agreement with applicable laws and regulations, good clinical practices, and ethical principles as described in the Declaration of Helsinki. This study was approved by the Institutional Review Board of Hanyang University Hospital (approval number: 2017-05-004-001). Each patient provided written informed consent of participation.
RESULTS
Patient Characteristics
Of the 345 patients examined, 304 patients were included in this study. Of these, 83 had nocturia (nocturia group) and 221 showed no nocturia (control group). The mean ages of the nocturia group and control group were 55.46±10.97 years and 45.19±12.56 years, respectively (P<0.001). There was no significant difference in sex ratio between the 2 groups (P=0.067). The prevalence of hypertension and DM was greater in the nocturia group than the control group (hypertension: 57.83% vs. 28.96%, respectively, P<0.001; DM: 33.73% vs. 7.24%, respectively, P<0.001). The waist-hip ratio (WHR) was 0.95±0.06 in the nocturia group and 0.93±0.57 in the control group (P=0.015), although there was no significant difference between the 2 groups in body mass index and neck circumference. The nocturia group scored higher on the IPSS/QoL questionnaire than the control group (7.32±0.80/1.24±0.14 points vs. 5.39±0.36/1.23±0.08 points, respectively, P<0.001) (Table 1).
Polysomnography
The total sleep time of the nocturia group was 233.83±86.32 minutes, which was shorter than that of the control group (275.08±83.78 minutes) (P<0.001), and sleep efficacy was lower in the nocturia group (74.02%±14.31%) than in the controls (80.99%±11.55%, P<0.001). Stage N3 sleep was 0.50%±1.75% in the nocturia group and 2.41%±5.73% in the control group (P=0.003). The apnea index (AI) and AHI were higher in the nocturia group than in the control group (AI: nocturia group, 22.76±28.45 events/hr; control group, 14.44±19.52 events/hr; P=0.004) (AHI: nocturia group, 39.19±32.58 events/hr; control group, 30.50±25.83 events/hr; P=0.016). The respiratory disturbance index was 42.52±31.00 for the nocturia group and 34.76±25.06 for the control group (P=0.025). Low O2 saturation levels during sleep were 77.61%±14.80% in the nocturia group and 81.50%±9.87% in the control group (P=0.009). Mean O2 saturation values were 94.08%±3.06% for the nocturia group and 95.40%±1.95% for the control group (P<0.001). Time spent in desaturation below 90% (T90), oxygen desaturation index≥3% (ODI3), and oxygen desaturation index ≥4% (ODI4) were significantly higher in the nocturia group. The degree of arousal was 42.33±22.19 in the nocturia group and 35.40±19.63 in the control group (P=0.014). ESS questionnaire results were not significantly different between the 2 groups, but PSQI questionnaire results were higher in the nocturia group (9.48±4.10) than in the control group (7.14±3.18) (P<0.001) (Table 1).
The results of PSG, when adjusted by age, hypertension, DM, and WHR, showed a significant difference in total sleep time, sleep efficacy, mean O2 saturation, T90, ODI4, and PSQI between the nocturia group and the control group (Table 2). Logistic regression analysis confirmed that age (odds ratio [OR], 1.052; P=0.004), DM (OR, 6.675; P<0.001), mean O2 saturation (OR, 0.650; P=0.017), ODI3 (OR, 1.193; P=0.010), ODI4 (OR, 1.136; P=0.014), and PSQI questionnaire score (OR, 1.264; P<0.001) affected nocturia independently (Table 3).
In propensity score matching analysis based on age, hypertension, and DM showed that IPSS (12.05±7.47 vs. 6.32±5.42, P<0.001), QoL (3.56±1.26 vs. 2.33±1.14, P<0.001) and PSQI (9.73±4.36 vs. 6.14±3.09, P<0.001) was significantly different between nocturia group and control group, respectively. Moreover, mean O2 saturation value in nocturia group was 94.18±3.08 and control group was 95.15±2.13 (P=0.033) (Table 4).
DISCUSSION
In present study, PSG results of patients with nocturia among OSA patients showed that total sleep time, sleep efficacy, mean O2 saturation, T90, and ODI4 were worse than that in OSA patients without nocturia. Moreover, our results indicate that mean O2 saturation, ODI3, ODI4, and the result of the PSQI questionnaire were independent factors for nocturia.
According to the International Continence Society, nocturia is defined as waking up to urinate at least once during sleep [6]. However, the number of times that urination is required to define a subject as having nocturia is controversial. According to a population study, at least 2 urination events constitute meaningful nocturia affecting well-being and perceived health. And they concluded that one urination per night does not identify subjects with interference from nocturia and is not a suitable criterion for clinically relevant nocturia [17]. Therefore, nocturia could be defined as 2 or more urination events during sleep [1,17]. In present study, nocturia was defined as 2 or more events of requiring urination during sleep in order to compare PSG characteristics prominently between the nocturia group and control group of OSA-suspected patients.
In a population-based survey of 19,165 adults, the overall prevalence of nocturia (≥1 void/night) in respondents 18 years of age and older was 48.6% in men and 54.5% in women. When nocturia was defined as 2 voids/night, the prevalence decreased to 20.9% in men and 24.0% in women [2]. In present study showed a higher prevalence of nocturia (≥2 void/night) (27.30%; male, 24.43%; female, 34.94%) than the previous study even though the high percentage of males (72.70%) and low mean age (48.00±12.96). These results may be due to our subjects being OSA patients.
Nocturia shows an increased incidence in elderly patients, and in patients with DM, hypertension, congestive heart failure, and urological diseases such as overactive bladder and benign prostate hyperplasia [18]. In particular, 59.6% of DM patients have reported nocturia more than twice [19]. The results of present study also confirm that age and DM are associated independently with nocturia.
There are 2 proposed mechanisms by which OSA affects nocturia. First, negative thoracic pressure due to airway obstruction increases venous return to the heart, resulting in increased atrial natriuretic peptide (ANP) and increased urine volume [20]. Second, hypoxia caused by OSA increases the amount of ANP secretion by increasing pulmonary vasoconstriction and right atrial transmural pressure [21]. Our results are consistent with the second proposed mechanism. The mean O2 saturation was significantly lower and the T90 and ODI4 values were significantly higher in the nocturia group than in the control group. Logistic regression analysis revealed that mean O2 saturation, ODI3, and ODI4 values influenced nocturia independently. Moreover, in propensity score matched analysis, mean O2 saturation in nocturia group was significantly lower than control group. In present study, we screened pulmonary diseases such as chronic obstructive pulmonary disease and asthma, which may affect hypoxia. There was no enrolled respiratory disease patient except for one asthma patient in nonnocturia group.
Usually, the AHI is used to assess the diagnosis and severity of OSA. OSA is defined as ≥5 AHI events per hour of sleep [22]. Most previous studies showing the association between OSA and nocturia evaluated OSA with AHI and assessed the association between AHI and nocturia [7,23]. However, in the present study, AHI did not appear to have a significant association with nocturia. On the other hand, the degree of desaturation showed a significant correlation with nocturia. ODI is an outcome of OSA and indicates the extent of oxygen desaturation. ODI3 (or 4) defined as the number of desaturations per hour of at least 3% or 4% from baseline [24]. ODI also shows the severity of OSA [25]. Therefore, our results suggest that OSA does not induce nocturia, but hypoxia caused by OSA induces nocturia.
According Finamore et al. [26], they reported that nocturia is associated with intermittent desaturation (ODI3) rather than severity and length of hypoxia represented by T90. However, in this study, although there was no significant difference in logistic regression, a significant difference in T90 was found between the 2 groups with adjusted for age, hypertension, DM, and WHR. In the previous study, the PSG parameters such as AHI, ODI and T90 are lower than those of the present study, and it can be inferred that the severity of sleep apnea is lower than that of this study. As ODI increases, T90 is also increased. This may be the reason for the difference in T90 between the 2 groups.
In a meta-analysis of five randomized controlled trials, Wang et al. [27] reported that CPAP improves nocturia and QoL in patients with OSA. However, previous studies have not evaluated the cause or mechanism of improvement of nocturia after CPAP treatment. In addition, Park et al. [14] reported that nocturia improved after surgical correction for OSA, but 27.03% of patients reported no improvement in nocturia. However, no comparative analysis of the degree of hypoxia was performed in this study. In the present study, we confirmed that hypoxia caused by OSA affects nocturia, and suggests that if OSA is corrected, nocturia will improve. However, patients who have nocturia after OSA treatment may need additional urological evaluation.
The present study had some limitations. There was no urological evaluation such as a voiding diary, uroflowmetry, or a urodynamic study. And confirming the change pattern of nocturia after correcting OSA in these patients, we could have a clearer assessment of the association between OSA and nocturia. Lack of evaluation of this part is another limitation. However, a relatively large number of patients were enrolled, and independent factors affecting nocturia were identified among OSA patients. Therefore, our results suggest that patients who are not expected to improve their nocturia can be screened.
In conclusion, hypoxia caused by OSA is considered as affecting factor to nocturia. And patients who have nocturia after correction of the OSA may need urological examination.
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