Oxidative stress and quality of life in elderly patients with obstructive sleep apnea syndrome: are there differences after six months of Continuous Positive Airway Pressure treatment?

CLINICAL SCIENCE

Oxidative stress and quality of life in elderly patients with obstructive sleep apnea syndrome: are there differences after six months of Continuous Positive Airway Pressure treatment?

Fabiana Yagihara; Ligia Mendonca Lucchesi; Vânia D'Almeida; Marco Túlio de Mello; Sergio Tufik; Lia Rita Azeredo Bittencourt

Universidade Federal de São Paulo (UNIFESP), Departamento de Psicobiologia, São Paulo/SP, Brazil

ABSTRACT

OBJECTIVES: This study evaluated the effect of Continuous Positive Airway Pressure treatment on oxidative stress parameters and the quality of life of elderly patients with obstructive sleep apnea syndrome.

METHODS: In total, 30 obstructive sleep apnea syndrome patients and 27 subjects without obstructive sleep apnea syndrome were included in this study. Both groups underwent quality of life and oxidative stress evaluations at baseline and after six months. Polysomnography was performed in both groups at baseline and a second time in the obstructive sleep apnea syndrome group after six months of Continuous Positive Airway Pressure treatment. All of the variables were compared between the control and obstructive sleep apnea syndrome groups in this prospective case-control study.

RESULTS: The baseline concentrations of the antioxidant enzyme catalase were higher in the obstructive sleep apnea syndrome group than the control group. After Continuous Positive Airway Pressure treatment, the obstructive sleep apnea syndrome group exhibited a reduction in the level of oxidative stress, as indicated by a decrease in the level of lipid peroxidation measured by the malondialdehyde (MDA) concentration [pre: 2.7 nmol malondialdehyde/mL (95% 1.6-3.7) vs. post: 1.3 nmol MDA/mL (0.7-1.9), p<0.01]. Additionally, improvements were observed in two domains covered by the SF-36 questionnaire: functional capacity [pre: 77.4 (69.2-85.5) vs. post: 83.4 (76.9-89.9), p = 0.002] and pain [pre: 65.4 (52.8-78.1) vs. post: 77.8 (67.2-88.3), p = 0.004].

CONCLUSION: Our study demonstrated that the use of Continuous Positive Airway Pressure to treat obstructive sleep apnea syndrome in elderly patients reduced oxidative stress and improved the quality of life.

Keywords: Continuous Positive Airway Pressure; Elderly; Obstructive Sleep Apnea Syndrome; Oxidative Stress; Quality of Life.

INTRODUCTION

Obstructive sleep apnea syndrome (OSAS) manifests as a reduction (hypopnea) or complete cessation (apnea) of airflow, which causes an increase in inspiratory effort that often culminates in arousal (1). OSAS is characterized by the collapse of the extrathoracic airway (2,3), a transient decrease in oxyhemoglobin saturation, hypercapnia, and consequent hyperventilation. These symptoms affect the objective and subjective qualities of sleep and trigger characteristic clinical symptoms, such as excessive daytime sleepiness (4,5). Several factors, including male gender, older age, obesity, alcohol use, otorhinolaryngological changes (6,7) and heredity, are associated with the prevalence, increased risk, and severity of OSAS (8,9).

The consequences of OSAS, such as accidents caused by excessive daytime sleepiness (10), increased risk of cardiovascular diseases (11) and mood and metabolic alterations (12,13), have been widely studied. OSAS also increases the generation of reactive oxygen species (ROS). The overproduction of ROS results in oxidative stress (OS), which results in damage to cellular structures, including lipids, membranes, proteins and DNA (14). OS produces a cascade of events that trigger inflammation, an increase in sympathetic tonus, vascular endothelial dysfunction, metabolic alterations, and/or increased platelet aggregation (15,16). The chronic intermittent hypoxia, sleep loss and fragmentation experienced by OSAS patients may be related to endothelial dysfunction due to the increases in the levels of inflammatory mediators, OS and coagulant activity. Endothelial dysfunction contributes to the development of atherosclerosis and OSAS-associated cardiovascular disorders. However, OSAS comorbidities and metabolic syndrome are also associated with endothelial dysfunction. OSAS may also induce or exacerbate various aspects of metabolic syndrome, such as glucose metabolism, cholesterol, inflammatory markers, and nonalcoholic fatty liver disease (17-21).

The use of Continuous Positive Airway Pressure (CPAP) is an effective treatment for OSAS because CPAP normalizes the sleep architecture, reduces subjective excessive daytime sleepiness and reverses other OSAS symptoms (22). CPAP treatment prevents hypoxia and oxygenation injury, decreases OS and inhibits the cascade of deleterious OSAS-induced consequences (23,24). Patients with severe OSAS and metabolic syndrome who exhibit good compliance with CPAP treatment may exhibit improved insulin sensitivity and reduced systemic inflammation, OS, and global cardiovascular disease risk (25).

Aging predisposes people to OSAS. The prevalence of OSAS is higher in elderly populations than in young adults (26). The prevalence of an apnea hypopnea index (AHI) >15 events per hour among 60- to 69-year-old males was 52.3% in São Paulo city, Brazil, and this frequency increased to 84.7% among 70- to 80-year-old males (27).

The literature highlights the positive effects of CPAP on excessive daytime sleepiness in adults and reports variable responses with respect to cardiovascular and cognitive functions; however, the impact of OSAS on the cardiovascular system in the elderly population is controversial (28,29).

The aims of this study were to compare OS parameters and the quality of life in elderly patients between individuals with and without OSAS and to evaluate the effect of CPAP treatment on OSAS patients.

METHODS

This study was approved by the ethics committee of the Universidade Federal de São Paulo (CEP: 1977/09). All of the patients signed an informed consent form.

Patients and Study Design

This prospective case-control study evaluated consecutive patients with suspected OSAS who were seen at the outpatient sleep clinic. The diagnosis of OSAS was confirmed using polysomnography (PSG) if the AHI was >20. Patients were compared with age-matched subjects without OSAS (AHI<10). These cut-off values were based on previous publications on OSAS in elderly patients (30,31).

The inclusion criteria were as follows: age between 60 and 75 years (32,33), male gender, and a body mass index (BMI) less than 35 kg/m². Subjects in the OSAS group exhibited clinical criteria of this syndrome (34) and an AHI of >20 events per hour; the AHI was <10/h in the control group. The protocol excluded individuals who had neurological or psychiatric diseases, sleep disorders other than OSAS, alcohol abuse and/or psychoactive drug use. Patients who had previously received treatment for OSAS were also excluded.

Subjects underwent an assessment protocol at baseline that used the following tools: a questionnaire that is routinely used in our sleep laboratory (35), the Epworth Sleepiness Scale (ESS) (36), a quality of life questionnaire (SF - 36) (37), laboratory tests and PSG. The PSG results and clinical symptoms divided the subjects into two groups (i.e., the presence or absence of OSAS). The OSAS group received six months of CPAP treatment, and the control subjects received no intervention. The OSAS group was submitted to PSG with CPAP at the end of the study. Both groups completed all of the other assessments at baseline at the end of the study (Figure 1).

Polysomnography

Full-night PSG was performed using a digital system (Embla® S7000, Embla Systems, Inc., Broomfield, CO, USA), and the following parameters were measured: electroencephalography, electromyography, electrocardiography, oral and nasal breathing (thermistor and pressure transducer), thoracic and abdominal respiratory effort (inductive plethysmography), snoring, oxyhemoglobin saturation, and body position. We used the Rechtschaffen and Kales criteria to score sleep (38). Respiratory events were assessed according to the American Academy of Sleep Medicine Task Force (1). Arousals (39) and periodic leg movements (40) were described according to the American Sleep Disorders Association criteria.

CPAP

All of the patients in the OSAS group underwent a full-night PSG to titrate the CPAP pressure. Each patient received a CPAP system (REMstar® Plus, Respironics, Inc., Murrysville, Pennsylvania, USA) after researchers determined the ideal pressure for treatment. The CPAP system had an hour meter to control the duration of the positive pressure.

The patients also participated in an educational program on CPAP use that included four visits by trained staff. Visits occurred one week and one, three, and six months after the initial treatment.

Laboratory Analysis

Venous blood for laboratory evaluations of OS parameters was collected in heparin-containing tubes in the morning after volunteers had fasted for twelve hours. Plasma and red blood cells were separated and properly stored for the evaluation of biochemical parameters (41). Spectrophotometry (Hitachi U-3900/3900H, Tokyo, Japan) was used to determine the levels of malondialdehyde (MDA, expressed in nmol MDA/mL), erythrocyte catalase (CAT) activity (expressed in U/mg hemoglobin), and superoxide dismutase (SOD) activity in erythrocytes (expressed as U/mg Hb).

A competitive immunoassay using direct chemiluminescence was used to determine the vitamin B12 and folate concentrations (ADVIA Centaur®/Siemens Healthcare Diagnostics, Inc., Deerfield, Illinois, USA). The folate concentrations are expressed as nmol/L, and the vitamin B12 concentrations are expressed as pmol/L.

High-performance liquid chromatography (HPLC) (Shimadzu with fluorescence detector RF-10AXL, Kyoto, Japan) with fluorometric detection and isocratic elution was used to measure the levels of plasma homocysteine (Hcy) and cysteine (Cys) (both are expressed in μmol/L). The uric acid values were measured using the uricase-enzymatic colorimetric method (Advia® 1650/2400/Siemens Healthcare Diagnostics, Inc., Deerfield, Illinois, USA). The results are expressed as mg/ dL. To determine the concentrations of vitamins C and E, we used an HPLC-UV system according to the Immundiagnostik method. The results are expressed in mmol/L.

Statistical Analysis

Statistical analysis was performed using SPSS version 13.0 for Windows. Descriptive analysis (means + standard errors) was used to characterize the groups. The results of the PSG, the questionnaire answers and the OS parameters were assessed using a general linear model (GLM) with repeated measures. This analysis assessed the effects of time, independent groups and control variables of interest. BMI was a covariate in this analysis to prevent bias because an association among obesity, OSAS and OS has been demonstrated previously.

We standardized the data using the Z score. The nonparametric Mann-Whitney test was used to compare independent groups, and the Wilcoxon test was used for repeated measures. Effect sizes (Partial Eta Squared - Eta²) and the observed power were also considered to prevent type I and type II errors. Statistical significance was set at 5% (p<0.05).

RESULTS

In total, 30 OSAS patients and 27 age-matched control subjects were included in this study. Both groups (control and OSAS) were homogeneous with respect to age (66.4+ 0.7 years vs. 66.4 + 0.7 years, respectively; p = 0.97), but the OSAS group had a higher mean BMI than the control group (25.1 + 0.7 kg/m² (control) vs. 27.9 + 0.7 kg/m² (OSAS); p = 0.004) (Table 1). The important comorbidities of both groups are presented in Table 2. No differences with respect to the frequencies of hypothyroidism, diabetes and dyslipidemia were observed between the groups; however, the prevalence of hypertension was higher in the OSAS group.

A multivariate analysis was used to evaluate the questionnaire responses at baseline, and the nonparametric Mann-Whitney test confirmed the results of this analysis. The OSAS group had a trend of higher ESS scores and worse quality of life, with lower scores for ''Functional Capacity'' (79.7+3.1 vs. 89.8 + 2.8; p = 0.02) and ''Pain'' (68.6 + 5 vs. 82.7 + 4.5; p = 0.04) compared with the control group. A tendency toward a lower score for ''General Heath'' was observed in the OSAS group (Table 3).

All of the factors exhibited overlapping confidence intervals in the repeated measures analysis of the two groups. However, because the groups were heterogeneous

Data are expressed as the mean+standard error (SE). BMI: body mass index; Sleep Lat: sleep latency; REM Lat: REM sleep latency; TST: total sleep time; SE: sleep efficiency; S1: stage 1; S2: stage 2; S3: stage 3; S3+4: stage 3 and 4; REM Sleep: rapid eye movement sleep; Wake: minutes awake; AI: arousal index; PLM: periodic leg movements; AHI: apnea/ hypopnea index; SpO₂: saturation of oxyhemoglobin; SpO₂<90%: cumulative time during which the saturation of oxyhemoglobin was below 90%. (GLM test).All of the OSAS patients of this study adhered to the CPAP protocol for at least four hours per night, and the pressures ranged from 8 to 15 cm H₂O. and because there was an insufficient number of cases, we used the Wilcoxon test and divided the level of significance by two. This test showed that there were improvements in ''Functional Capacity'' (p = 0.002) and ''Pain'' on the SF-36 (p = 0.004) (Table 3).

Multivariate analyses of all of the PSG variables at baseline demonstrated a high effect size (Eta² = 0.79) and a strong observed power (p = 1.00). BMI was used as a covariant. Relative to the control group, the OSAS group exhibited significant differences with respect to variables related to light sleep (increased percentage in stage 2 of NREM sleep) (60.3 + 2.5% vs. 53 + 2.3%; p = 0.04) and higher arousal rates (27.1 + 2.4 per hour vs. 11.8 + 2.2 per hour; p<0.01). In addition, the OSAS group had a higher AHI (37.8+ 2.3 per hour vs. 5.3 + 2.1 per hour; p<0.01) and lower minimum and mean oxyhemoglobin saturation levels (76.7+ 2% vs. 87.9 + 1.8%; p<0.01 and 91.2 + 0.8% vs. 94.2 + 0.8%; p<0.05, respectively) than controls. The OSAS group also spent more time with oxyhemoglobin saturation levels below 90% (22.9 + 4.6% vs. 1.19 + 3.3%; p<0.01) (Table 1).

PSG was performed a second time in the OSAS group to evaluate the effect of the CPAP treatment. The PSG performance after treatment revealed a decrease in the percentage of stage 1 NREM sleep (5.8 + 0.6% vs. 4.3 + 0.5%; p<0.01), a tendency toward an increase in the percentage of REM sleep (18.1 +1.4% vs. 22 +1.5%; p = 0.06), a decrease in minutes spent awake (102.7+17.3 min vs. 65 +11 min; p = 0.03), a decrease in therateofawakenings(25.6+ 2.9 per hour vs. 10.4+ 1.2 per hour; p<0.01), a reduction in the AHI to within the normal range (36.6 + 3.4 per hour vs. 4 + 0.9 per hour; p<0.01), and a reduction in the duration of oxyhemoglobin saturation levels below 90% (20.9 + 8.6% vs. 0.8 + 0.4%; p<0.05) compared with baseline values. These changes were associated with objective improvements in sleep quality (Table 4).

TheCATconcentrationsatbaselinewerehigherinthe OSAS group than the control group [115.3 U/mg Hb (95% 88142) vs. 105.6 U/mg Hb (95% 67.8-143), respectively; p = 0.004]. A significant increase in the vitamin C concentration was observed for the control group [pre 56.5 mmol/L (95% 50.4-62.7) vs. post 69.4 mmol/L (95% 63.2-75.7); p<0.01] and for the OSAS group [pre 51.6 mmol/L (95% 44.0-59.2) vs. post 62.4 mmol/L (95% 54.7-70.1); p<0.01] at the final examination. Higher CAT activity was observed in the OSAS group compared with the control group [140.3 U/mg Hb (95% 115.0-165.0) vs. 50 U/mg Hb (95% 15.1-85.0)] at the final evaluation. The use of CPAP treatment by the OSAS group decreased the level of lipid peroxidation, which was expressed in terms of the MDA concentration [pre: 2.7 nmol MDA/mL (95% 1.6-3.7) vs. post: 1.3 nmol MDA/mL (0.7-1.9); p<0.01] (Table 5).

No significant correlations between variables were observed.

DISCUSSION

Our study demonstrated that the use of CPAP to treat OSAS in elderly male patients contributed to a reduction in OS and improved the quality of life. Oxidative damage and OSAS may be related to aging. Similarly, a relationship may exist between the reduction in antioxidant capacity and OSAS after CPAP treatment. We demonstrated that CPAP was able to reverse OS, as demonstrated by decreases in the MDA concentrations. We also found that the CAT concentration increased in the OSAS group after treatment. These results suggest that OSAS may overload a patient's antioxidant capacity, which increases CAT activity. However, this augmentation of the antioxidant enzyme activity was insufficient to cope with OSAS-induced OS, and the lipid peroxidation levels were elevated in the OSAS group prior to CPAP treatment. These results suggest that lipid peroxidation may be an important pathological event for these patients. Six months of CPAP treatment increased the level of catalase activity, which suggests that the antioxidant defense system was activated, and this mechanism was able to reduce the level of lipid peroxidation levels in OSAS patients during this period.

The association between aging and antioxidant capacity is not well established, and no consensus has been reached regarding the influence of aging on antioxidant capacity (42,43). The increased CAT activity and reduced lipid peroxidation observed in this study indicate the importance of evaluating OS markers in OSAS patients. Therefore, future studies should focus on improving the antioxidant capacity of these patients.

An increase in the vitamin C concentration was observed in both groups at the time of re-assessment relative to the baseline levels. However, the concentrations were within the normal range. These findings suggest that alterations in the observed OS parameters are not related to vitamin C availability.

The mean vitamin E concentrations in both groups (OSAS and controls) were within the normal range (15 to 40 μmol/ L), which suggests that there is no effect of age on this parameter.

One reason for the controversy regarding OS in the literature may be that there are many protocols for assessing OS, and researchers do not frequently follow the same protocol. In addition to the variability in protocols, most of the measures of OS markers are indirect measures, which are less accurate (42-44).

The OSAS group exhibited a worse quality of life for two domains of the SF-36 (''Functional Capacity'' and ''Pain'') compared with the control group at baseline. The p-value (0.051) for the difference in the ''General Health'' domain was not statistically significant, but a trend toward improvement in this domain was observed. Therefore, repeating this study with a larger sample size may detect an improvement in this domain. CPAP treatment improved ''Functional Capacity'' and ''Pain''. Improvement reflected by the SF-36 after CPAP treatment has been reported previously in adults (45). However, OSAS did not sufficiently impact the quality of life in the elderly in a previous study (46). The improvement of pain as measured by the SF-36 in our study suggests an association between OSAS and the activation of inflammatory pathways and a reversal of OSAS by CPAP treatment (47).

The OSAS group exhibited fragmented sleep, increased light sleep, reduced slow-wave sleep, and reduced REM sleep on the PSG. These results are consistent with those reported in the literature (48).

CPAP treatment tended to decrease ESS scores, suggesting that this treatment is effective and supporting its probable association with the improvement in the quality of sleep observed in previous studies (36,49).

No differences in hypothyroidism, diabetes, and dyslipidemia were observed between the two groups; however, the prevalence of hypertension was higher in the OSAS group. All of our patients and control subjects received hypertension treatment, and blood pressure levels were controlled for as a comorbidity. This difference has been reported previously, and it highlights the association between OSAS and cardiovascular diseases (11). This association may influence OS. OS is associated with endothelial dysfunction and metabolic syndrome, which leads to cardiovascular diseases. However, OSAS is frequently complicated by metabolic syndrome (50). OSAS and metabolic syndrome may exert negative synergistic effects on the cardiovascular system through multiple mechanisms (e.g., intermittent hypoxia, sleep disruption, and activation of the sympathetic nervous system and inflammatory mediators) (51), which may be related to OS.

Our study demonstrated that elderly patients with OSAS may benefit from CPAP treatment, which improved sleep parameters, contributed to the reversal of OS and enhanced the patients' quality of life.

ACKNOWLEDGMENTS

This work was supported by grants from the Associação Fundo de Incentivo a Psicofarmacologia (AFIP) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (2007/06232-0 to FY and Centro de Pesquisa, Inovação e Difusão [CEPID] no. 98/14303-3 to ST). ST, VD'A, MTMello and LRAB received a fellowship from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). The authors would like to thank Laura de Siqueira Castro and Altay Lino de Souza from the Departamento de Psicobiologia/Universidade Federal de Sao Paulo for their valuable suggestions and help with the statistical analysis.

AUTHOR CONTRIBUTIONS

Yagihara F, Lucchesi LM, D'Almeida V, de Mello MT, Tufik S, and Bittencourt LRA were responsible for the study concept and design, the analysis and interpretation of the data, the drafting of the manuscript, and the critical revision of the manuscript for important intellectual content; they had full access to all study data and take responsibility for the integrity and accuracy of the data analysis. Yagihara F, Lucchesi LM, and D'Almeida V were responsible for the acquisition of the data. Castro LS and Souza AL were responsible for the statistical analysis. Tufik S and Bittencourt LRA obtained the funding. D'Almeida V, de Mello MT, Tufik S and Bittencourt LRA were responsible for administrative, technical, and material support. Tufik S and Bittencourt LRA were responsible for the supervision of the study.

Received for publication on February 7, 2012

First review completed on February 13, 2012

Accepted for publication on February 16, 2012

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Publication Dates

• Publication in this collection
  29 June 2012
• Date of issue
  2012

History

• Received
  07 Feb 2012
• Accepted
  16 Feb 2012
• Reviewed
  13 Feb 2012