| | Nasal continuous positive airway pressure treatment reduces systemic oxidative stress in patients with severe obstructive sleep apnea syndromeReceived 4 July 2007; received in revised form 8 October 2007; accepted 28 October 2007. Abstract ObjectiveTo evaluate whether nasal continuous positive airway pressure (nCPAP) reduces oxidative stress in patients with severe obstructive sleep apnea (OSA) syndrome. ConclusionsPatients with severe OSA syndrome presented increased systemic oxidative stress. A single night of nCPAP treatment significantly reduced the levels of oxidative stress in patients with severe OSA syndrome, and this reduction was maintained at least after two months of nCPAP treatment. 1. Introduction  Obstructive sleep apnea (OSA) syndrome is a condition characterized by the occurrence of repetitive episodes of partial or complete obstruction of the upper airway and may lead to decreased blood oxygenation and fragmentation of the sleep cycle. These episodes of hypoxia/re-oxygenation may induce the generation of oxygen free radicals [1]. Free oxygen radicals or reactive oxygen species (ROS) are highly reactive molecules playing pivotal roles in the pathophysiology of different diseases as neurodegenerative disorders, chronic inflammatory disease, and cancer [2]. Studies have provided evidence that supports an increase of oxidative stress in OSA. Schulz et al. and Dyugovskaya et al. detected an increase in the production of ROS in OSA [3], [4], while Barcello et al. and Lavie et al. demonstrated an increase of plasma lipid peroxides [5], [6]. Furthermore, Saarelainen et al. reported increased oxidized LDL – autoantibodies in OSA patients [7] and Carpagnano et al. observed elevated 8-isoprostane levels in the exhaled breath condensate in OSA patients [8], [9], while Yamamuchi et al. found urinary 8-hydroxy-2′-deoxyguanosine (8-OhdG) excretion in the severe OSA patients [10]. In our previous studies, we have shown that patients with OSA present elevated values of ROS and reduced values of antioxidant capacity [11], [12]. The aim of the present study was to evaluate the effect of nasal continuous positive airway pressure (nCPAP) on the levels of systemic oxidative stress in patients with severe obstructive sleep apnea (OSA) syndrome, both acutely after the first night of nCPAP titration and after two months of nCPAP treatment. 2. Materials and methods 2.1. Subjects All adult men and women (n =155) who were referred to the Sleep Disorders Clinic of the Respiratory Medicine Department of the University of Thessaly during a period of six months because of snoring or other symptoms of respiratory disturbance during sleep and excessive daytime sleepiness were considered for participation in the study. Exclusion criteria were the following: (1) a diagnosis of cardiovascular disease, lung disease, chronic renal failure or diabetes mellitus; (2) use of corticosteroids or antibiotics for the four weeks proceeding recruitment in the study; (3) autoimmune, neuromuscular or genetic disorders; and (4) symptoms or signs of acute or chronic inflammatory disorders or recent infections (within the past 4 weeks prior to polysomnography). Patients with arterial hypertension who received appropriate treatment and had levels into the normal range during their examination were included in the study. Patients with a diagnosis of cardiovascular disease other than controlled arterial hypertension were excluded from the study. One hundred and twenty two people were initially considered eligible for the study. All of them gave an interview where a physician asked them questions about their age, smoking habits and symptoms such as excessive daytime sleepiness and snoring. Patients also completed the Epworth Sleepiness Scale (ESS), a standardized questionnaire for the evaluation of daytime sleepiness. Physical examination and simple spirometry followed the initial evaluation. Blood pressure, fasting blood glucose and lipid levels were additionally measured routinely in all subjects. All eligible patients were subsequently submitted to an initial polysomnography followed by a second night for nasal continuous positive airway pressure (nCPAP) titration; a final evaluation was performed two months after the use of nCPAP at home. The study was approved by the University of Thessaly Research Committee and all patients provided written informed consent. 2.2. Polysomnography During polysomnography, electroencephalogram, electrooculogram, and electromyogram of the submandibular and pretibial muscles were recorded simultaneously. Ventilatory airflow at the nose and mouth was registered with thermistors. The breathing movements of the chest and abdomen were monitored by inductive plethysmography. The arterial oxygen saturation (SaO2) was measured transcutaneously with pulse oximetry at the fingertip of the patient. Finally, an electrocardiogram was obtained. All data were registered on a computerized polysomnography with capability for analog registration (Alice 4 Diagnostic Device, Respironics, Marietta, Georgia, USA). Analysis of sleep stages was performed manually at 30-s intervals according to the criteria of Rechtschaffen and Kales [13]. An obstructive apnea was diagnosed if complete cessation of oronasal flow occurred in the presence of thoracoabdominal breathing movements. If neither oronasal flow nor breathing efforts of the chest and abdomen could be detected this was scored as a central apnea. Hypopnea was defined as a reduction of the respiratory amplitude by greater than 50% with regard to the preceding effort signals; alternatively, when a clear amplitude reduction of a validated measure of breathing during sleep did not reach the above criterion, another criterion for hypopnea was considered: association of amplitude reduction with either an oxygen desaturation of >3% or an arousal [14]. All apneas and hypopneas were required to have a duration of at least 10s. The apnea/hypopnea index (AHI) was obtained by dividing the total number of events with the total sleep time. An AHI of more than five events per hour of sleep was considered as diagnostic of OSA. Desaturation during sleep was defined as a fall in baseline oxygen saturation of ⩾4%. The oxygen desaturation index (ODI) was derived from the number of episodes of desaturation per hour of total sleep time. An arousal was defined by a modification of the 3s rule of the American Sleep Disorders Association as an abrupt shift in EEG frequency including theta, alpha, and/or frequencies greater than 16Hz; during REM an arousal was scored according to 3s EEG changes, with submental EMG amplitude increases. Arousal index (AI) was the number of arousals per hour. [15]. 2.4. Assessment of oxidative stress levels Blood samples were analyzed immediately after their collection by an investigator (K.C.) who was not aware of the clinical features of the patients or the results of the other parameters. Oxidative stress was evaluated with the measurement of free oxygen radicals with a commercially available method (D-ROMs test, Free Radical Analytical System, DIACRON, Grosseto, Italy), as previously described [11]. This is a spectrophotometric method that assesses the overall oxidative stress in biological fluids by measuring the total levels of hydroperoxides. Hydroperoxides are generated by the oxidative attack of reactive oxygen species on a number of organic substrates (e.g. lipids, peptides, and aminoacids). The serum samples are centrifuged and 20μL of serum sample are diluted in 1mL of acetate-buffered solution (pH, 4.8). Hydroperoxide groups react with the transition metal ions liberated from the proteins in the acidic medium and are converted to alkoxyl and peroxyl radicals according to the Fenton reaction. The results of this method are expressed in conventional units (Carratelli Units, UCarr) and 1UCarr corresponds to 0.8mg/L hydrogen peroxide (H2O2). In normal subjects UCarr values range from 250 to 300. Values outside this range are considered indicative of an alteration in the equilibrium between pro-oxidant and antioxidant capabilities of subjects. Values greater than 300UCarr indicate a condition of oxidative stress [16]. The levels of oxidative stress, as expressed by the D-ROMs test, have been extensively evaluated by our group. Briefly, we have shown that D-ROMs are related to the severity of OSA [11] and that they represent a marker for the differentiation between exudative and transudative pleural effusions [17] and a possible marker for the evaluation of disease severity in patients with idiopathic pulmonary fibrosis [18]. 2.5. Statistical analysis Data are presented as means±standard error of the mean (SEM). Comparisons of oxidative stress levels between two groups were performed with student’s t-test, while comparisons among three or more groups were performed with one-way analysis of variance (ANOVA) with an appropriate post hoc test (Bonferroni). Correlations between values of oxidative stress and nocturnal polysomnography markers were evaluated using Pearson’s correlation coefficient. A p value <0.05 was considered statistically significant. In order to define independent predictors of oxidative stress levels in our population, a stepwise multiple linear regression model was created using oxidative stress levels as the dependent variable and age, current smoking, BMI, ESS score, AHI, ODI, AI, lowest SaO2, and mean SaO2 as the dependent variables. All data were analyzed with the Statistical Package for Social Sciences (SPSS, version 12.0, Chicago, IL, USA). 3. Results From the 122 subjects initially recruited, thirty patients with an AHI 15–29events/h (n=30) were not included for further analysis. The remaining 92 subjects were classified into two groups with respect to AHI and nCPAP therapy: those with AHI<15 (n=46) and those with severe OSA, i.e. with AHI⩾30 (n=46). The characteristics of the subjects in the two groups are presented in Table 1. The two groups had no difference in age and smoking habits; however, patients with severe OSA presented higher BMI. | | |  | | AHI<15 | AHI⩾30 | p value | |
|---|
| Female/male | 5/41 | 1/45 | 0.091 | | | Age (years) | 45.70±1.71 | 49.17±1.68 | 0.149 | | | BMI (kg/m2) | 28.66±0.59 | 32.16±0.73 | 0.001 | | | Current smokers | 14 | 18 | | | | PYS of current smokers | 32.36±6.90 | 37.95±4.34 | 0.480 | | | SBP (mmHg) | 122.39±3.46 | 127.24±1.76 | 0.215 | | | DBP (mmHg) | 72.52±2.42 | 76.85±1.96 | 0.168 | | | Glucose (mg/dl) | 93.37±3.60 | 95.37±2.53 | 0.650 | | | Cholesterol (mg/dl) | 188.28±2.20 | 189.26±1.80 | 0.731 | | | LDL (mg/dl) | 113.72±2.90 | 117.03±1.50 | 0.313 | | | HDL (mg/dl) | 47.46±3.07 | 44.74±1.22 | 0.412 | | | Triglycerides (mg/dl) | 135.48±2.45 | 137.46±3.55 | 0.647 | | | ESS score | 7.39±0.62 | 10.78±0.70 | 0.001 | | | AHI (events/h) | 7.51±0.69 | 63.09±2.86 | 0.001 | | | ODI (events/h) | 9.62±1.01 | 66.02±3.21 | 0.001 | | | AI (events/h) | 15.36±0.10 | 61.93±2.92 | 0.001 | | | Lowest SaO2 (%) | 86.63±0.66 | 68.17±1.60 | 0.001 | | | Mean SaO2 (%) | 91.11±0.30 | 83.65±0.85 | 0.001 | | | D-ROM before diagnostic NPSG (UCarr) | 319.28±12.66 | 357.57±13.07 | 0.038 | | | D-ROM after diagnostic NPSG (UCarr) | 328.09±11.76 | 371.83±12.83 | 0.014 | | | | |
3.3. Determinants of oxidative stress levels Patients with severe OSA were obese (defined as a mean BMI>30), in contrast with patients from the control group (AHI<15). However, when patients were divided into obese and non-obese groups each according to BMI, we did not find any statistically significant differences in the morning levels of D-ROM both in the control group (AHI<15 and BMI<30: 360.53±15.54UCarr vs. AHI<15 and BMI⩾30: 352.00±24.51UCarr, p=0.760) and in the severe OSA group (AHI⩾30 and BMI<30: 320.50±16.85UCarr vs. AHI⩾30 and BMI⩾30: 318.63±17.40UCarr, p=0.945). Furthermore, in the group of severe OSA patients (AHI⩾30) the morning D-ROM value after using nCPAP for one night and for a period of two months did not differ when the patients were divided to non-obese (BMI<30: nCPAP for one night 286.75±17.58UCarr vs. nCPAP for a period of two months 293.86±12.40UCarr, p=0.743) or obese (BMI⩾30: nCPAP for one night 304.33±11.46UCarr vs. nCPAP for a period of two months 293.63±7.72UCarr, p=0.442). Additionally, in the stepwise multiple linear regression model, the only significant independent predictor of oxidative stress levels the morning after the diagnostic NPSG in the whole study population was the arousal index (AI; R=0.311, p=0.003). 4. Discussion In the present prospective cross-sectional study we have shown that patients with severe OSA (AHI⩾30) present increased levels of systemic oxidative stress compared to subjects with AHI<15. Furthermore, we have shown that nCPAP provided an acute reduction in systemic oxidative stress levels in severe OSA patients after a single night of nCPAP application, and this reduction was maintained after a period of two months of nCPAP treatment. Free oxygen radicals or reactive oxygen species (ROS), as measured in peripheral venous blood samples by the D-ROM test, were enhanced in OSA patients. We have previously used this method for the assessment of oxidative stress levels in OSA patients [11]. In the present study we have shown that patients with severe OSA syndrome (characterized by elevated AHI) had increased values of oxidative stress. It is known that OSA patients have several reasons to have oxidative stress. First the OSA patients present repetitive episodes of hypoxia/re-oxygenation during the night, which may facilitate free radical production and the free oxygen radicals can propagate lipid peroxidation and vascular damage [3], [19]. Second, the reperfusion/re-oxygenation that follows the hypoxic period during an apnea or a hypopnea activates a variety of cells including endothelial cells, leucocytes, and lymphocytes, and propagates inflammatory processes [20] that free radical production [7], [21], [22]. Third, catecholamine-induced changes, secondary to increased sympathetic nerve activity in OSA, can promote lipid peroxidation [23]. The last fact is that OSA is characterized by long-term sleep deprivation, which activates lipid peroxidation, inhibits antioxidant defense systems, and inactivates mitochondrial enzymes [24], [25]. Indeed, our statistical analysis showed that the arousal index was the best predictor of oxidative stress in severe OSA patients. On the other hand, some studies provide evidence for non increased oxidative stress in OSA patients. Wali et al. have shown no differences in susceptibility of LDL to oxidative stress [26] and Svatikova et al. have shown that patients with moderate – severe OSA do not have evidence for greater oxidative stress and lipid peroxidation than healthy normal subjects [27]. Although those earlier OSA patient studies failed to provide evidence for oxidative stress, more recent studies demonstrated that obstructive sleep apnea syndrome is an oxidative stress disorder [6], [10], [19], [28], [29]. The correlations that we found between values of oxidative stress in severe OSA patients with polysomnography markers (such as lowest oxygen saturation of hemoglobin) are in agreement with those of recent studies and suggest that overnight intermittent hypoxia is the major trigger factor for free oxygen radicals production on sleep apnea. Nasal continuous positive airway pressure was found to be effective in reducing the levels of oxidative stress in our severe OSA patients. Interestingly, the reduction of oxidative stress levels was observed acutely (after one night with nCPAP) and was preserved in the long-term (i.e., after a period of two months with nCPAP treatment). These results are consistent with other studies suggesting that nCPAP was effective in suppressing OSA-associated changes in redox status, providing evidence that apneic events might alter redox biology in OSA patients [3], [4], [5], [6], [30], [31], [32]. More recently, Hernadez et al. observed that plasma concentrations of malondialdehyde in OSA patients were reduced after treatment [33]. A major point in our study in contrast to the findings of previous studies is that we have shown that the reduction in systemic oxidative stress was achieved after a single night of nCPAP therapy, therefore showing that nCPAP induces an acute reduction of oxidative stress. It is well established that oxidative stress is related to many factors, including obesity [34], smoking [35], age [36], hypertension [37], hyperlipidemia [38], and diabetes [39]. In our study there were no differences in age and smoking habits between the two groups. The exclusion criteria such as inflammation, cardiovascular disease, lung disease, diabetes mellitus, or neuromuscular or genetic disorder, allowed us not to have influence on oxidative stress in our sample by these disorders. The only parameter that needed more statistical analysis was BMI, being increased in the severe OSA group. When we divided the two groups by BMI lower and greater than 30 (i.e., obese vs. non-obese) we showed that the levels of oxidative stress did not differ between the corresponding subgroups. Furthermore, the results of the multiple linear regression analysis showed that the only independent predictor of morning levels of oxidative stress levels was the arousal index, whereas BMI was not a significant predictor. Finally, oxidative stress parameters decreased after CPAP treatment without any changes in BMI occurring during these time intervals. The above evidence suggests that obesity had no influence on oxidative stress levels in our population sample. Another issue that needs to be commented in the present study is that a significant proportion of the subjects referred to our Sleep Clinic (92 of 155, 59%) did not present any metabolic abnormalities. This is in contrast with previous studies reporting a prevalence of metabolic syndrome of 60% [40] to 87% [41]. However, patients referred to our outpatient Sleep Clinic do not present severe comorbidities, such as severe COPD or severe decompensated congestive heart failure, as those patients are routinely submitted to polysomnography as inpatients, and this may account for the relatively low prevalence of metabolic syndrome in our study. In conclusion, in the present study we have confirmed that oxidative stress is increased in patients with severe OSA, and that the severity of OSA was significantly correlated with the oxidative stress. Treatment with nCPAP acutely reduced the levels of oxidative stress after a single night of intervention and this reduction was maintained for two months of nCPAP treatment. Further studies are warranted on the long-term effects of nCPAP on systemic oxidative stress in patients with severe OSA syndrome. 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Respiratory Medicine Department, University of Thessaly Medical School, University Hospital of Larissa, Larissa 41110, Greece  Corresponding author. Tel.: +30 6944780616; fax: +30 2410670240.
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