Abstract
Introduction: Sleep disturbances and cardiovascular autonomic dysfunction are major complications of hemodialysis (HD). The goal of this study is to identify clinical, heart rate variability (HRV) or laboratory parameters that are independently associated with subjective sleep quality. Patient and methods: Forty-six stable HD patients filled out sleep questionnaires – Pittsburgh sleep quality index (PSQI), Athens insomnia scale (AIS), and Epworth sleepiness scale (ESS). In addition, they received analyses of 5-minute HRV twice, in lying posture before and after HD. We also recruited 50 healthy subjects who received 5-min HRV. Results: The patients with end-stage renal disease have a high rate of poor sleep quality according to PSQI, AIS, and ESS. The activities of total power (0–0.5 Hz), high-frequency power (HF, 0.15–0.40 Hz), low-frequency power (0.04–0.15 Hz), and very-low-frequency power (0.003–0.04 Hz) in HD patients are obviously lower than that in the healthy people. The poor sleepers (PSQI > 5) show lower heart rate, higher HF and variance before HD, but did not show a significant difference after HD. There is no significant difference between HRV and global score of AIS, but the insomnia group (AIS > 5) has higher BMI. These patients with sleepiness (ESS > 9) only reveal lower hemoglobin, although the global score of ESS reveals no significant relationship with HRV. Conclusion: HD patients have a high rate of poor sleep quality and autonomic dysfunction. Greater attention for the evaluation of sleep quality is needed for the better care of HD patients.
INTRODUCTION
Sleep disturbances are common problems in end-stage renal disease (ESRD) patients.Citation1 Several studies have shown that the prevalence of subjective sleep problems ranges from 50% to 88.5% among these patients.Citation2–6 Taiwan-based studies showed a high prevalence of insomnia (66.6%) and poor sleep quality (74.4%) in ESRD patients.Citation7,Citation8
Many conditions may cause sleep disturbances in these patients, including constraints in life, metabolic abnormalities, dietary restrictions, dyspnea, fatigue, nocturnal cramps, advanced age, hypocapnia accompanied by metabolic acidosis, neuropathic pain, and emotional problems.Citation9 Sleep disorders appear to be part of the ESRD and manifest as sleep-disordered breathing/sleep apnea,Citation10,Citation11 excessive daytime sleepiness (EDS),Citation12,Citation13 periodic limb movement disorder (PLMD), and restless legs syndrome (RLS).Citation14,Citation15
It is well established that patients with ESRD have a diminished quality of life, as well as increased sleep complaints.Citation13 The poorer sleep quality is also independently linked to higher mortality rate.Citation16 Recently, the role of cardiovascular autonomic dysfunction has been emphasized as an independent risk factor for intradialytic hypotension or even sudden death in ESRD.Citation17,Citation18 The spectral analysis of heart rate variability (HRV) has been proven to be a potent, noninvasive, sensitive, and reproducible tool for the diagnosis of cardiovascular autonomic dysfunction in ESRD.Citation19–21 It is well established that HRV can be divided into total power (TP, 0–0.5 Hz), high-frequency power (HF, 0.15–0.40 Hz), low-frequency power (LF, 0.04–0.15 Hz), and very-low-frequency power (VLF, 0.003–0.04 Hz) components.Citation22 The HF component is equivalent to respiratory sinus arrhythmia and is thought to reflect vagal control of heart rate.Citation23 The TP, LF, or variance are components mediated by both sympathetic and vagal efferent activity.Citation24 The ratio of LF to HF (LF/HF) and LF in normalized units (LF%) are thought by some investigators to mirror sympathovagal balance or reflect sympathetic modulation, the HF in normalized units (HF%) responses to sympathetic inhibition.Citation22,Citation25
There are close interactions between sleep and autonomic nervous system. In general, wakefulness and non-rapid eye movement (non-REM) sleep are characterized by a vagal predominance. REM sleep is associated with profound sympathetic activation.Citation26,Citation27 Heart rate decreases throughout the sleep period compared with wakefulness, and this decrease is associated with increases in the HF and decreases in the LF component of HRV during light sleep (stage II sleep) and deep sleep (stage III–IV, slow-wave sleep), which were reversed during REM sleep.Citation28
Focusing on the sleep quality of hemodialysis (HD) patients is now of increasing importance. There are not many reports about sleep disturbance and autonomic dysfunction in ESRD patients. At the same time, there is not much information on HRV parameters correlating with the HD process that includes the immediate pre- and postdialysis periods. We hypothesize that there is a link between daily autonomic function and nocturnal sleep disturbance in ESRD patients. We assume that HRV components are sensitive to the HD process. We therefore decide to use sleep questionnaires and HRV as noninvasive tools to assess sleep quality and the changes of autonomic function before and after HD.
SUBJECTS AND METHODS
The protocol of this study was approved by the Chang Bing Show-Chwan Memorial Hospital Research Ethics Review Committee (No. IRB-D008-B). All patients provided informed consent before participation.
Patients
Forty-six HD patients (24 males, 22 females), aged 61.70 ± 14.19 years, who took part in the research were all from the Department of Nephrology in Chang Bing Show-Chwan Memorial Hospital. All patients received daytime dialysis with the total hours per week varying from 8 to 13.5 h. The inclusion criteria were as follows: patients who (1) received maintenance HD >3 months; (2) were of age ≥20 years, and (3) provided informed consent. The exclusion criteria were as follows: presence of (1) autoimmune disease, malignancy, active infection, uncontrolled heart failure, or significant inflammation; (2) acute medical or surgical condition that required hospitalization or operation within the previous month; and (3) arrhythmia. We also recruited 50 healthy subjects, gender- and age matched (25 males and 25 females, aged 62.52 ± 12.02 years), as control group who were free of physical illness and were not taking any medication at the time of this study. Other exclusion criteria included a personal or family history of a sleep disorder, shift work, heavy caffeine (>350 mg per day), alcohol (>5 standard drinks per week), or having major life stress.
Measurement of Sleep Quality
Sleep quality in this study was measured by three sleep questionnaires (translated into Chinese) – Pittsburgh sleep quality index (PSQI), Athens insomnia scale (AIS), and Epworth sleepiness scale (ESS). The PSQI questionnaire with 19 questions measures the sleep quality of the previous month. From the answers, seven components (each scored from 0 to 3) were calculated: subjective sleep quality, sleep latency, duration, efficiency, disturbance, use of sleep medications, and daytime dysfunction. From the sum of seven component scores, the global PSQI score was calculated (0–21). A patient with a global PSQI score ≤5 is considered to be a good sleeper and those with a value >5 is considered to be a poor sleeper.Citation29 The Chinese version of the PSQI has been used for the study of sleep quality in Taiwan's HD patients.Citation7,Citation8 The AIS was used to assess sleep complaints and to identify possible cases of clinically significant insomnia. The AIS consists of eight items. The first five items cover nighttime symptoms of insomnia (sleep induction, awakenings during the night, final awakening, total sleep duration, and sleep quality) and three items probe daytime consequences of disturbed sleep (well-being, functioning capacity, and daytime sleepiness).Citation30 A study for diagnostic validity of AIS suggested that a cutoff score of 6 provides an acceptable sensitivity and specificity.Citation31 The Chinese version of the ASI had satisfactory reliability and validity in insomnia diagnoses.Citation32 The ESS is a simple, self-administered questionnaire that has been shown to provide a measurement of daytime sleepiness. The range of scores on the ESS is 0–24, with a higher score reflecting greater sleepiness and a normal score being below 9.Citation33 The Chinese version of the ESS has also been used in Taiwanese HD patients.Citation7 In this study, patients completed this questionnaire by themselves or under the assistance of sleep technologists.
Measurement of Laboratory Data
Blood samples were obtained from all patients fasting for at least 8 h just before the midweek dialysis treatment. The biochemical data were taken at the central lab of Chang Bing Show-Chwan Memorial Hospital.
HRV Analysis
Two 5-minute frequency-domain analysis using an HRV analyzer (WG-MD-ANSA01, WeGene Co. Ltd., Taipei, Taiwan, Republic of China) was performed before and after HD at approximately morning time of the day on each subject while the subject lay quietly and breathed normally. The 50 healthy subjects also received 5-minute HRV once by the same method. We performed HRV twice due to possible autonomic dysfunction in these HD patients. The power spectrum was subsequently quantified into standard frequency-domain measurements as defined previously,Citation22 including R–R interval (RR), VLF, LF, HF, TP, variance, LF%, HF%, and LF/HF.
Statistical Analysis
Sociodemographic and clinical characteristics were summarized using a descriptive statistical method. Continuous variables considered in this article, including age, BMI, and clinical characteristics, were reported as mean ± standard deviation. Categorical variables including gender, regular habits, and chronic diseases were reported as numbers and percentage. The relationship of mean differences between groups (before HD vs. control group, after HD vs. control group, good sleeper vs. poor sleeper, insomnia vs. non-insomnia, and sleepiness vs. non-sleepiness) were analyzed with Wilcoxon rank sum test. Analysis of variance (ANOVA) followed by the Scheffe test was used for comparison of group differences. All data were analyzed using the statistical package SAS for Windows, version 9.1 (SAS Institute Inc., Cary, NC, USA).
RESULTS
Patient Characteristics
The dialysis duration in the HD group is 2.57 ± 2.20 years. BMI in the HD group is 24.66 ± 4.12. In addition, the rates of hypertension, type 2 diabetes mellitus (DM), and stroke history are 63.04%, 73.91%, and 6.52%, respectively. Other blood and biochemical analysis results are shown in .
Table 1. Sociodemographic and clinical characteristics of the hemodialysis patients
HRV of HD Group and Healthy Group
Between control and before the start of dialysis of HD group, significant differences (p < 0.05) are observed in VLF, LF, HF, TP, and variance. The LF% before start of dialysis is also decreased significantly when compared with control. The results mean that the HD patients have lower autonomic dysfunction including sympathetic and parasympathetic tones. Similarly, between control and after the end of dialysis of HD group, significant differences are found in the above factors. But there is no significant difference in HRV between before the start and after the end of dialysis ().
Table 2. Comparison of heart rate variability between control group, before and after hemodialysis
Further comparing the HD patients with and without hypertension, there are no obvious differences in HRV parameters before and after dialysis (). However, in analysis for diabetic history, we find that the diabetic patients have decreased LF before HD condition. At the same time, many autonomic parameters including LF, variance, LF%, and LF/HF are found to be obviously lower in the HD patients with DM history after the dialysis condition ().
Table 3. Comparison of heart rate variability between non-hypertension and hypertension history, before and after hemodialysis
Table 4. Comparison of heart rate variability between non-diabetes and diabetes history, before and after hemodialysis
Pittsburgh Sleep Quality Index and Heart Rate Variability
The global score of PSQI is found to be 7.63 ± 3.65 (). Good sleep quality (global PSQI score ≤5) is observed in 11 HD patients and a poor sleep quality (global PSQI score >5) in the remaining 35 patients. The rate of patients with poor sleep quality is up to 76.09% in the HD group. There is no significant difference between the two groups in age, gender, HD duration, diabetes, and hypertension as well as biochemical data (data not shown). However, RR, HF, and variance before start of dialysis are higher in the poor sleeper than in the good sleeper ().
Table 5. The global scores of PSQI, AIS, and ESS
Table 6. Comparison of some demographics, laboratory data, and autonomic indexes between good sleepers and bad sleepers by PSQI
Further evaluating the relationship between HRV and the seven components of PSQI, we find significance in two items. First, in the subjective quality of sleep, the variance before start of dialysis and HF after end of dialysis are higher in the quite poor sleeper group than in the very good sleeper group (). Second factor is about the sleep latency; the variance before start of dialysis and HF and variance after end of dialysis are higher in <15 min group than 16–30 min latency (). The other autonomic parameters do not show obvious relationship with the two items (data not shown).
Table 7. The relationship between autonomic indexes and mean scores of subjective sleep quality in PSQI
Table 8. The relationship between autonomic indexes and mean scores of sleep latency in PSQI
Athens Insomnia Scale and Heart Rate Variability
The global score of AIS is 7.57 ± 4.30 (). The number and rate of insomnia (AIS > 5) in HD patients are seven and 15.22%, respectively. There is no significant difference in all the parameters compared, except BMI, which is higher in the insomnia group than in the non-insomnia group ().
Table 9. Comparison of some demographics, laboratory data, and autonomic indexes between non-insomnia and insomnia by AIS
Further analyzing the relationship between HRV and eight items of AIS, we first find that the HF before start of dialysis is significantly higher in the considerable “problem” group than in the “no problem” group in the components of awakenings during the night (). Then, we find that the HF before start of dialysis is higher in the “not earlier” group than in the “little earlier” group in the item of final awakening (). Lastly, the HF% before start of dialysis is higher in the “slightly decreased” group than in the “markedly decreased” group in the components of well-being during the day (). Other insignificant results are not further described.
Table 10. The relationship between autonomic indexes and mean scores of awakenings during the night in AIS
Table 11. The relationship between autonomic indexes and mean scores of final awakening in AIS
Table 12. The relationship between autonomic indexes and mean scores of well-being during the day in AIS
Epworth Sleepiness Scale and Heart Rate Variability
The global score of ESS is 5.54 ± 4.23 (). The rate of daytime drowsiness (ESS > 9) in HD patients is up to 69.57%. There is no remarkable difference in all parameters tested, except in Hb, which is lower in the sleepiness group than in the non-sleepiness group ().
Table 13. Comparison of some demographics, laboratory data, and autonomic indexes between non-sleepiness and sleepiness by ESS
DISCUSSION
Cardiovascular autonomic dysfunction is a frequent complication of chronic renal failure.Citation34 A reduction of HRV in ESRD patients has been demonstrated in some earlier reports,Citation19–21,Citation35 whereas some other groups reported increased LF power.Citation36 This discrepancy may be related to clinical or methodological differences. The LF of HRV is a marker of sympathetic oscillatory regulation whereas HF is that of vagal oscillatory regulation. According to our data, HRV including VLF, LF, HF, TP, and variance are significantly decreased in both before the start of and after the end of dialysis analysis when compared with the control. However, there is no significant difference for the HRV parameters between before the start and after the end of dialysis. Tong et al. reported a significant decrease in LF/HF ratio in HD patients for 3 h; they have excluded diabetic patients from their study groups.Citation21 However, our study group included patients with diabetes up to 73.91%. The diabetic history has been known to be a strong factor that affects the autonomic function.Citation37 Our data also demonstrated that diabetic HD patients had lower autonomic function, after dialysis period. So the difference between our result and that of other studies may be associated with the type 2 diabetic history in most HD patients.
One significant finding of this study is that the patients with ESRD have a high rate of poor sleep quality according to PSQI, AIS, and ESS. With regard to sleep quality, the rate of bad sleeper (PSQI > 5) is up to 76%. A few other studies showed 67%,Citation9 71%,2 80%,7 and 89%.Citation4 Our results are in agreement with those of previous studies reporting a high percentage of poor sleepers in the HD population. We did not find that dialysis duration is an independent predictor of global score for PSQI. A few previous studies reported a negative correlation between age and global PSQI score.Citation3,Citation4 In our study, we did not find any correlation, which is in agreement with a few earlier reports.Citation2,Citation6 So the relationship between age and sleep quality is still controversial in ESRD patients. Two previous studies have shown higher PSQI scores in patients who have received HD therapy for a long period of time.Citation3,Citation4
We found that the percentage of insomnia (AIS > 5) in HD patients is 15%. In one study, the presence of RLS is the strongest significant independent predictor of the AIS score.Citation38 Although RLS is strongly linked with ESRD,Citation14,Citation15 we did not further evaluate the relationship between the two in this study. Regarding the factors that can influence insomnia, we found that the insomnia group in HD patients has higher BMI. In fact, overweight may cause many sleep disorders, including obstructive sleep apnea, alveolar hypoventilation, and restrictive ventilatory impairment.Citation39 Based on the report of Paparrigopoulos et al., the independent predictors associated with insomnia are female sex and depression as measured by the Hospital anxiety and depression scale.Citation40 We do not find similar significance in gender factor and did not screen depression in the HD group. As PSQI, AIS, and ESS use different parameters for diagnosing insomnia and general sleep quality separately, we prefer to use all the three methods in our study.
In the evaluation of EDS, we found that the rate of sleepiness (ESS > 9) is high up to 70%, which is compatible to major complaints by patients undergoing ESRD from previous reports.Citation12,Citation13 Sleep apnea, RLS/PLMD, subclinical uremic encephalopathy, and elevated parathyroid hormone may play important roles to cause EDS.Citation10–15,Citation41,Citation42 At the same time, we find that HD patients with sleepiness have obviously lower Hb level. In fact, hyperhemoglobinemia is very common in HD patients. The mean Hb of this study is 10.04 ± 1.25 g/dL; other studies showed 10.9 ± 1.42 g/dL,Citation6 11.2 ± 1.5 g/dL,Citation39 and 10.2 ± 1.44 g/dL.Citation7 The lower Hb concentration caused cerebral metabolism dysfunction and EDS may be the hypothetical explanation.Citation43 The associated factors of EDS in HD patients need further evaluation.
We find that RR, HF, and variance before start of dialysis are higher in the poor sleeper (PSQI > 5). Further analysis in the component of major items shows that the variance before start of dialysis and HF after end of dialysis is higher in the “quite poor” group than in the “very good” group. At the same time, the variance before start of dialysis and HF and variance after end of dialysis are higher in <15 min group than 16–30 min latency. On the contrary, according to AIS and HRV analysis, some differences of HRV parameters in items of awakening during the night, final awakening, and well-being during the day are found. The reasons for these changes are unexplained but may be suspected due to the fact that the HD patients nearly have abnormal autonomic function.Citation19–21,Citation34 Also, another reason is that autonomic function fluctuates depending on sleep dynamics when non-REM sleep is accompanied by an augmentation of parasympathetic tone with depression of sympathetic activity, and REM sleep shows reverse change.Citation26,Citation27 The autonomic function is even synchronized with REM/non-REM ultradian sleep rhythm.Citation44 Our daily short-term HRV measurements can partially answer some sleep problems in HD patients.
There are certain limitations to our study. First, emotional factors are involved in determining the quality of sleep and we did not perform specific questionnaires to assess the exact prevalence of depression, a factor commonly involved in sleep disorders. Second, our study did not use continuous HRV during HD or sleep, which may cause some difference in the autonomic evaluation. Third, our study also did not evaluate the prevalence of comorbid medical conditions such as cardiovascular and bone diseases linked to dialysis. Certain sleep medications or antihypertensives may have influenced sleep quality or autonomic function and we did not control the use of these medications in our patients. Finally, our patients did not receive clinical polysomnography, so the final diagnoses of sleep disorder were not established.
Our findings have important clinical applications. As there is a strong correlation between patients with ESRD and sleep disorders, doctors should perform a regular assessment of the patients for this problem. Further studies are necessary to investigate the causes of poor quality of sleep and investigate methods to increase sleep quality in this population. Future studies will be directed toward understanding the neurological correlates of sleep disturbances in patients with renal diseases.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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