Effect of continuous positive airway pressure on oxidative stress accompanied by obstructive sleep apnea

Introduction: In obstructive sleep apnea (OSA), there is increased oxidative stress. Aim of this work: This study aimed to examine the effect of continuous positive airway pressure (CPAP) on oxidative stress occurring in OSA. Participants and methods: The present study was carried out on 40 individuals classified into four groups: group I included 10 control participants, group II included 10 obese individuals without OSA, group III included 10 patients with mild to moderate OSA, and group IV included 10 patients with severe OSA. Sleep study was carried out, and Thiobarbituric acid-reactive substance and superoxide dismutase enzyme were measured. Results: Thiobarbituric acid-reactive substance was significantly increased, but superoxide dismutase was significantly decreased in group IV, and CPAP led to an improvement in this condition. Conclusion: OSA leads to increased oxidative stress that improved with the use of CPAP.


Introduction
Obstructive sleep apnea (OSA) is characterized by repetitive interruption of ventilation during sleep caused by collapse of the pharyngeal airway associated with ongoing ventilatory eff ort [1,2]. Factors that increase for the risk of developing this disorder include age, male sex, obesity, family history, menopause, craniofacial abnormalities, and certain health behaviors such as cigarette smoking and alcohol use [2]. OSA is quantifi ed on the basis of the apnea-hypopnea index ( AHI). According to the American Academy of Sleep Medicine recommendations, OSA is defi ned as AHI more than 5, and it is classifi ed as mild OSA with AHI of 5-15, moderate OSA with AHI of [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30], and severe OSA with AHI more than 30 [3,4], leading to excessive daytime sleepiness, which can be assessed subjectively using the Epworth Sleepiness Scale [5][6][7] and treated with positive airway pressure [8]. Oxidative reactions are coupled with the continuous generation of highly reactive and potentially cytotoxic reactive oxygen species ( ROS). Under normal conditions, the ROS produced during the course of metabolism are contained by the natural antioxidant system that protects the functional and structural molecules against ROS-mediated modifi cations, thereby preventing cytotoxicity and tissue damage [9]. Th us, oxidative stress results from an imbalance between radical-generating and radicalscavenging systems, that is OSA is characterized by recurrent nocturnal obstruction of the upper airway. Each episode of airway obstruction is usually followed by a marked decrease in arterial oxygen saturation, which rapidly normalizes after ventilation resumes. Th us, OSA patients experience repeated episodes of hypoxia and normoxia. During the hypoxic phase, cells adapt to a low oxygen environment; however, the reoxygenation phase causes a sudden increase in oxygen in the cells. Th is reoxygenation phase is considered to result in the production of ROS and the promotion of oxidative stress [10,11] or reduced activity of antioxidant defenses, or both [12].

Aim of this work
Th e aim of this work was to assess the plasma levels of thiobarbituric acid-reactive substances (TBARS) and superoxide dismutase (SOD) enzyme in patients with OSA and correlate their levels with the severity of the disease, and to study the eff ect of continuous positive airway pressure (CPAP) therapy on their levels in severe cases after 1 and 7 days of treatment.

Aim of this work
This study aimed to examine the effect of continuous positive airway pressure (CPAP) on oxidative stress occurring in OSA.

Participants and methods
The present study was carried out on 40 individuals classifi ed into four groups: group I included 10 control participants, group II included 10 obese individuals without OSA, group III included 10 patients with mild to moderate OSA, and group IV included 10 patients with severe OSA. Sleep study was carried out, and Thiobarbituric acid-reactive substance and superoxide dismutase enzyme were measured.

Exclusion criteria
(1) Cardiovascular diseases: for example, hypertension, ischemia, and arrhythmia. (2) Pulmonary diseases: for exa mple, COPD, bronchial asthma, and lung cancer. Th e participants were subjected to the following: (1) Detailed assessment of personal history including age, sex, occupation, and special habits (smoking and alcohol). (2) Detailed assessment of medical history, with a special focus on symptoms of OSAS such as snoring, restless sleep, and excessive daytime sleepiness, and surgical history of any pre vious ENT operations. (3) Subjective evaluation of daytime sleepiness using Th e Epworth Sleepiness Scale. (4) Th orough clinical examination including measurement of blood pressure and heart rate, height and weight for calculation of BMI, measurement of neck circumference, and ENT examination to exclude major anatomical deformity. Informed consents were obtained from all participants.

Results
Th ere was a signifi cant increase in the OSA index in group IV compared with the other groups, but there was an insignifi cant diff erence between groups I, II, and III. Percent of total sleep less than 90% was signifi cantly increased in group IV compared with the other groups. Group III showed a signifi cant increase compared with groups I and II, but there was an insignifi cant diff erence between groups I and II, and the above two parameters improved signifi cantly during CPAP autotitration. Serum TBARS were signifi cantly increased in group IV compared with group II; also, they were signifi cantly increased in groups III and IV compared with group I, but there was an insignifi cant diff erence between group III and groups II and IV, and also between groups I and II. It was signifi cantly decreased after 1 and 7 days of CPAP treatment compared with before treatment. Serum SOD was signifi cantly decreased in group IV compared with group II; also, it was signifi cantly decreased in groups III and IV compared with group I, but there was an insignifi cant diff erence between group III and groups II and IV, and also between groups I and II. It was signifi cantly increased after 1 and 7 days of CPAP treatment compared with before treatment (Tables 1-8).

Discussion
OSA syndrome is characterized by recurrent episodes of partial or complete pharyngeal collapse (hypopneas or apneas) occurring during sleep. It is a growing     health concern aff ecting up to 5% of middle-aged men and women in the general population. Th is is a serious health hazard, being recognized as an independent risk factor for hypertension, arrhythmias, and coronary heart disease [13].
OSA patients experience repeated episodes of hypoxia (which can last for 10 s to as long as 2 min) and normoxia (2-3 min). During the hypoxic phase, cells adapt to a low oxygen environment. However, the reoxygenation phase causes a sudden increase in oxygen in the cells. Th is reoxygenation phase is considered to result in the production of ROS and the promotion of oxidative stress [11].
Th e present study showed that oxidative stress markers (TBARS and SOD) were signifi cantly diff erent between the four groups studied. Plasma levels of TBARS were signifi cantly lower in the control group than in OSA patients, whereas plasma levels of SOD were signifi cantly higher in the control group than in the OSA patients. Th ese results were in agreement with those reported by Lavie et al. [14]; the morning plasma level of TBARS was found to be signifi cantly higher in OSA patients with and without cardiovascular di sease (CVD) than in nonapneic controls. Wysocka et al. [15] confi rmed the above results. Th ey found decreased SOD activity in the overweight OSAS patients compared with the overweight controls, but no signifi cant diff erence in TBARS between OSAS patients and controls. However, among obese participants, decreased SOD activity was found in obese OSAS patients compared with obese controls and increased TBARS concentration in obese OSAS patients compared with obese controls. Liu et al. [16] showed that plasma SOD activity was signifi cantly lower in 107 patient s with OSAHS than 69 control participants. Indices of oxidative stress increased in OSA patients for several reasons; fi rst, sleep apneic patients are subjected repetitively each night to disturbed hypoxic sleep. Th ese episodes of hypoxia/ reoxygenation could facilitate free radical production, which would lead to lipid peroxidation and vascular damage. Second, increased infl ammatory leukocytes in OSA patients have been shown to trigger free radical production. Th ird, catecholamine-induced changes, secondary to increased sympathetic nerve activity in OSA, can promote lipid peroxidation. Finally, longterm sleep deprivation has been shown to activate lipid oxidation, inhibit antioxidant defense systems, and inactivate mitochondrial enzymes [17,18]. In contrast to our fi ndings Alzoghaibi et al. [19] reported no signifi cant diff erence between severe OSA patients and controls in both SOD and TBARS. Savtikova et al. [20] measured plasma indices of oxidative stress and lipid peroxidation: TBARS, ox idized LDL, and isoprostanes in 41 me n with moderate-severe OSA without other diseases and in 35 matched controls before sleep, and then after treatment with CPAP. Plasma levels of the three markers were similar in  patient s with moderate-severe OSA and in the controls. Th e authors proposed that the absence of any evidence for oxidative stress in OSA patients is unlikely to be explained by a compensatory increase in the activity of antioxidative enzymes in these patients. Although their study was not designed to measure antioxidants, two preliminary reports suggested that antioxidant defense mechanisms are unaff ected or even decreased in OSA. Wali et al. [21] reported no signifi cant diff erences in glutathione peroxidase and catalase activities in red blood cells in hypoxic and non-hypoxic patients and Christou et al. [22] reported that in 14 patients with severe OSA (AHI>20), antioxidant capacity was reduced. Th erefore, the lack of increased oxidative stress and lipid peroxidation in sleep apneic patients suggests that in the absence of signifi cant comorbidities, sleep apnea does not initiate the generation of oxidative stress or lipid peroxidation. Th e main fi nding of this study is that short-term CPAP therapy in patients with severe OSA notably improved oxidative stress markers in these patients. We found a signifi cant decrease in the plasma levels of TBARS after one night and seven nights of CPAP therapy and a signifi cant increase in the plasma levels of SOD after one night and seven nights of CPAP therapy. In most studies, the CPAP treatment had been administered for periods ranging from 3 to 12 months, which may be bothersome to the patients. Th ere is negligible information in the literature on the eff ects of shortterm CPAP treatment on oxidative stress. Our results are consistent with those found by Singh et al. [23], who studied the eff ect of CPAP therapy for two nights on oxidative stress markers (lipid peroxidation by TBARS and antioxidant capacity by total reduced glutathione enzyme) in 20 male OSA patients. Th ey repeated the measurement of both markers after 45 days of oral intake of antioxidant vitamins C and E. Th e baseline TBARS level was signifi cantly higher in OSA patients compared with the control participants and CPAP therapy for two nights reduced the TBARS level signifi cantly. Th e baseline glutathione levels were signifi cantly lower in OSA patients compared with the control participants, and CPAP therapy for two nights led to a signifi cant increase in the levels.
Not in complete agreement with our results, Alzoghaibi et al. [24] concluded that CPAP therapy decreases the levels of lipid peroxidation in OSA patients, but may not aff ect antioxidant defense after they studied the eff ects of one night of CPAP therapy on oxidative stress (lipid peroxidation) levels and the antioxidant activities of SOD in 34 hypertensive patients with severe OSA. However, Savtikova et al. [20] showed that the level of TBARS in sleep apneics was similar to that in controls after 4 h of eff ective treatment with CPAP.

Conclusion
OSA leads to increased oxidative stress, which was improved with the use of CPAP.