Obstructive sleep apnea (OSA) is characterized by repeated episodes of breath cessation (apnea) and reduced ventilation (hypopnea) and is recognized as an important cause of medical morbidity and mortality. Data from the Wisconsin Sleep Cohort Study have estimated that the prevalence of OSA with an apnea/hypopnea index (AHI) ≥5 events per hour among adults was 9% for women and 24% for men.1 The disorder is associated with a wide range of significant medical consequences, including hypertension,2 cardiovascular diseases,3 and psychological effects.4
The key risk factors for OSA include age, excess body weight, sex, and craniofacial abnormalities.5 Smoking, a predisposing factor for pulmonary and respiratory diseases, is highly prevalent in patients with OSA.6 Several studies have indicated that smoking may act as a risk factor for developing OSA.6-9 Moreover, a recent study has suggested that there is a synergistic effect between smoking and OSA to increase cardiovascular risk,10 further indicating some kind of interaction between smoking and OSA. Furthermore, studies have revealed that OSA might be responsible for the addiction to nicotine.11,12 In the following sections, we review the current evidence that links smoking to OSA and discuss some potential mechanisms proposed for these links.
Early in 1988, the study by Bloom et al13 demonstrated that smokers were more likely to snore. The finding has been further confirmed by other studies.14-18 Of note, these studies seem to reach a similar conclusion, that smoking is an independent risk factor for snoring, despite the different degree of the association among studies. Since snoring is considered to be a common symptom and a preclinical form of OSA, it is reasonable to speculate that smoking may be associated with OSA. The main studies concerning the link between smoking and OSA in the last two decades are summarized in Table 1.
A large population-based epidemiologic study was carried out by Wetter et al7 to determine whether current and former cigarette smoking acted as potential risk factors for sleep-disordered breathing (SDB). Totally, 811 subjects were recruited and underwent overnight polysomnography (PSG) in the study. Current smokers were more likely than never smokers to snore (odds ratio (OR) 2.26, 95% confidence intervals (CI) 1.46-3.49) and had a significantly greater risk of any SDB (OR 1.64, 95% CI 0.94-2.86), particularly of moderate or worse SDB (OR 2.24, 95% CI 1.03-4.86). Of interest, all these ORs increased, rather than decreased, after adjustment for confounding effects. Unadjusted OR suggested an association between former smoking and SDB, but the trend disappeared after adjustment for confounders, indicating that smoking cessation might attenuate the adverse effects of smoking. Additionally, a dose-response association was found between smoking and SDB. Heavy smokers, who smoked ≥40 cigarettes per day, were more likely to present mild (OR 6.74, 95% CI 1.20-37.89), moderate or worse (OR 40.47, 95% CI 2.37->50) and any (OR 8.38, 95% CI 1.68-41.94) SDB, compared with never smokers. Both mild and moderate smokers were at increased risk of having SDB. Although the 95% CI for the dose-response relationship was broad, heavy smokers were still more likely to experience SDB.
Another study conducted by Kashyap et al6 enrolled 108 OSA patients and 106 in a matched control group to investigate the prevalence of smoking in patients with OSA and to determine whether smoking was an independent risk factor for OSA. The prevalence of smoking in patients with OSA was found to be 35%, whereas it was only 18% in patients without OSA. When adjusting for age, gender, body mass index (BMI), and the number of alcoholic drinks per week, the risk for OSA was 2.5 times greater in current smokers than in former smokers and nonsmokers combined (OR 2.5, P=0.0049). Such differences were also demonstrated between current and former smokers alone (OR 2.8, P=0.0028), but did not exist in the comparison between former and never smokers (OR 1.2, P=0.64). Two other epidemiological studies examined risk factors for OSA. Moreno et al8 demonstrated that smoking was an independent risk factor for OSA in 10 101 truck drivers using the Berlin Questionnaire (OR 1.16, P=0.014). Neruntarat et al9 investigated office-based workers and people referred to the hospital in a rural area of central Thailand and found that the prevalence of OSA was two times higher in smokers than in non-smokers (OR 2.1, 95% CI 1.6-2.3).
A cross-sectional case study conducted by Hoflstein19 showed that there was a higher prevalence of current smokers and greater pack-years of smoking among subjects with AHI >50/hour, and the heaviest smokers (≥30 pack-years) presented a higher AHI when compared to never smokers (26.3±28.3 and 19.7±23.9, respectively). In this study, the author failed to find a clear relationship between smoking and AHI. He drew the conclusion that the effects of smoking might be attenuated by confounding effects such as sex, age, and BMI, and the relationship between smoking and OSA, if it existed, was relatively weak.
In addition, two other studies found a dose-response relationship between smoking and nocturnal hypoxia. Casasola et al20 showed that the index of the magnitude and duration of oxyhemoglobin desaturation during sleep was significantly higher in current smokers than in non-smokers (P=0.017), indicating that current smokers experienced more severe nocturnal hypoxia. Also a significant correlation between the pack-year index and the nocturnal hypoxia index as well as the carboxyhemoglobin concentration was demonstrated. In the study of Conway et al,21 current smokers who had pack-years ≥15 were more likely to spend more than 5% of total sleep time at a saturation of oxyhemoglobin lower than 90% (OR 1.9, 95% CI 1.21-2.97). Both current and former smokers had a higher arousal index compared to never smokers. The author suggested that smoking severity might play a role in sleep fragmentation, particularly among current smokers.
SMOKING IS A RISK FACTOR FOR OSA
Currently, several possible patho-physiological mechanisms have been evoked to explain the possible association between smoking and OSA, including smoking-induced upper airway inflammation, the effects of nicotine on upper airway muscles, and “rebound effect” due to nightly short-term nicotine withdrawal or all above.
Smoking and airway inflammation
Increased nasal resistance in smokers was demonstrated in an earlier study.22 Even passive smoking was associated with increased nasal airflow resistance and apparently altered mucociliary clearance.23 Indicators of nasal obstruction, which have been suggested to be associated with OSA,24 may be at least partly due to elements of smoking-induced chronic mucosal inflammation such as cellular hyperplasia, mucosal edema, thicker epithelium, and impaired cilia function.25,26 The association between smoking and upper airway inflammation was further confirmed by a recent cross-sectional study involving 2523 subjects, which found a causal link between chronic smoking and reduced nasal cavity dimensions, low airflow and a less-compliant nasal mucosa.27 Additionally, Virkkula et al28 showed that smokers were more likely to experience severe snoring at a younger age with increased nasal obstruction, lower nasal volumes after decongestion as well as a longer soft palatal length both in upright and supine positions. Decreased nasal patency together with a longer soft palate might contribute to more severe snoring in smokers. Moreover, the authors evaluated snoring and symptoms related to OSA after nasal surgery (septoplasty or septorhinoplasty) in smokers and never smokers. Snoring intensity did decrease in all subjects while daytime sleepiness only improved in subjects with higher nasal resistance. However, when analyzed by smoking status, no significant improvement was found in nocturnal breathing or arousal after nasal surgery. Nonsmokers had lower nasal resistance before nasal surgery, which may have decreased the possible benefit of nasal surgery. And subjects may have other craniofacial abnormalities which could not be improved by one single surgery. Another possible explanation was that chronic mucosal changes, induced by long-term smoking, were already present in the upper airways, and could not be totally reversed by nasal surgery.
The detrimental effects to respiratory systems attributable to smoking are not limited to the upper airways. Smoking has been reported to be associated with decreased lung function,29 an increased rate of respiratory infections,30 and obstructive airway diseases such as chronic obstructive pulmonary disease (COPD) and asthma.31 Through these possible mechanisms, smoking might further affect breathing during sleep. And some of these adverse effects, in turn, may increase vulnerability to OSA.32 For instance, the efficiency of the diaphragm was enhanced in patients with low lung volumes, which might generate more negative inspiratory pressure in the thorax and upper airway, predisposing the pharynx to collapse. In chronic bronchitis, increased sputum production may contribute to increased upper airway resistance resulting in snoring and OSA.32
Effects of nicotine on upper airway muscles
During sleep, both the tonic activity of the upper airway dilator muscles and their respiratory related activity decrease more than inspiratory muscle activity due to sleep-induced loss of compensatory tonic input to the upper airway dilator muscle motor neurons.33 Early in 1963, nicotine was shown to increase ventilation by exciting neural structures located close to the ventrolateral surface of the medulla.34 In the 1980s, studies in animals showed that nicotine decreases upper airway resistance.35,36 One of these studies showed that nicotine stimulated upper airway muscles, including the genioglossus, more than it does the diaphragm.35 Based on the observation that nicotine increases ventilation and upper airway muscle activity in animals, a trial of nicotine chewing gum in eight subjects was carried out. The results demonstrated that the administration of nicotine chewing gum before sleep decreased the number of obstructive and mixed apneas during sleep with reduced apnea duration in the first two hours of sleep but did not affect central apneas.37 Given that nicotine levels in the blood when chewing gum or when smoking cigarettes peak within five or ten minutes after administration and decline to one-third of their peak levels in 60 minutes,38 the stimulant effects of nicotine may be transient. They then found that obstructive and mixed apneas increased again in the second hour compared to the first hour. Similar effects of nicotine may also exist in current smokers. Thus, as the nicotine levels continue to decline throughout the night, sleep apnea may increase due to the “rebound effect” of nicotine withdrawal per se, or the interaction between the respiratory effects of smoking and nicotine withdrawal. Of course, the effects of nightly nicotine withdrawal do not necessarily exist in all smokers and the individual sensitivity to the effects of nicotine cannot therefore be excluded. However, the exact effects of nicotine on OSA might include smoking-induced inflammation, the effect of obesity on upper airway muscles, “rebound effect” of nicotine withdrawal or all of the above.
SMOKING AS A PROMOTING FACTOR FOR OSA
As mentioned above, Casasola et al20 and Conway et al21 demonstrated that current smokers were more likely to experience longer durations of hypoxia, which might worsen the consequence of OSA. Bonsignore et al39 showed that smokers with OSA experienced significantly lower PaO2 during wakefulness and lower SaO2 during non-rapid eye movement (NREM) sleep. Remodeling of the small airways and decreased lung function induced by chronic smoking40 may be one of the possible mechanisms. Considering the effects of sleep on ventilation, the remodeling of airways induced by chronic smoking could worsen the ventilation perfusion mismatching, contributing to the small but significant changes in arterial saturation seen especially during rapid eye movement (REM) sleep.41 Smoking produces a marked increase in carboxy-hemoglobin (HbCO), causing the oxyhemoglobin dissociation curve to shift to the left. Such a shift may lead to difficulties in tissue oxygenation due to the increased affinity of the pigment for oxygen.20 In addition, chronic exposure to smoking leads to decreased hypoxia sensitivity, blunted hypoxia-induced arousal and an impaired ability to autoresuscitate from apnea,42-44 which facilitates longer durations of apneas with desaturation. The most common interpretation of these alterations involves abnormal functioning of the peripheral chemoreceptors, but altered central modulation of the chemoreceptors due to adverse effects of smoking on the developing brain during the fetal period cannot be excluded.45 However, to date, decreased hypoxia sensitivity has only been found among infants who experienced prenatal exposure to cigarette smoke.
Smokers have been reported to have a high prevalence of sleep disturbance.11 This was further confirmed by two more studies46,47 which showed that current smokers experienced a longer latency to sleep onset, lower sleep efficiency and had a shift toward lighter stages of sleep. Additionally, Conway et al21 observed that current smokers with pack-years ≥15 exhibited a higher arousal index after considering gender, BMI, age, AHI, smoking status and pack-year categories. This might be explained by nightly nicotine withdrawal related sleep disturbance. Earlier studies have reported decreased sleep quality with frequent and extended awakenings during complete nicotine abstinence.48,49 Similarly, nightly nicotine withdrawal experienced by current smokers may increase sleep instability. Nicotine acts through the stimulation of nAChRs in the central nerve system to increase the release of neurotransmitters, which have been implicated in regulation of the sleep wake cycle.50 The reduced levels of nicotine throughout the night may be associated with decreased release of the relevant neurotransmitters, leading to sleep instability. Thus the stimulant effects of nicotine, nightly withdrawal and possible psychological disturbance may be plausible explanations for the association between smoking and sleep disturbance.7 Under this situation, smoking may interact with OSA to exacerbate sleep fragmentation, resulting in decreased sleep quality and more severe daytime sleepiness.
EFFECT OF SMOKING ON THE CLINICAL OUTCOME OF OSA
Smoking and cardiovascular injury of OSA
OSA is an independent risk factor of cardiovascular diseases3,51 and so is chronic smoking.52 The major underlying mechanisms predisposing patients to cardiovascular diseases (CVD) in OSA include oxidative stress, an abnormal inflammatory response and endothelial dysfunction.53,54 Long-term smoking induces CVD based on similar mechanisms.55,56
Recently a preliminary study has been conducted by Lavie et al10 to investigate oxidative stress and circulating inflammatory markers in OSA patients. They found that smokers with OSA showed significantly higher levels of circulating triglycerides and inflammatory markers including C-reactive protein, ceruloplasmin, and haptoglobin and lower levels of high-density lipoprotein (HDL) cholesterol than non-smoking OSA patients, indicating a synergistic effect between cigarette smoking and OSA to increase cardiovascular risk. In particular, the highest level of ceruloplasmin and the lowest level of HDL were found in smokers with severe OSA, suggesting that patients with severe OSA who smoked were at a greater cardiovascular risk than smokers with mild-moderate OSA and patients who did not smoke. In addition, a study carried out by Bonsignore et al39 indicated that smoking OSA patients had lower baroreflex sensitivity only during wakefulness and a larger cardiovascular variability during wakefulness and sleep.
Smoking and endocrine outcome of OSA
Kirbas et al57 evaluated the impact of OSA and smoking on total serum testosterone levels in 96 men. They found lower serum total testosterone levels in OSA patients and negative correlation with AHI. The results were identified in earlier studies.58,59 However, they did not find that serum testosterone was correlated with pack-years of smoking, in contrast to some earlier reports which demonstrated higher serum testosterone levels in current smokers.60,61 The authors thought that perhaps a higher prevalence of OSA in current smokers lead to the contradictory findings regarding testosterone levels. Further, the results might highlight the interaction between OSA and cigarette smoking, which needs further studies.
It has been confirmed that orexin-A, a neuropeptide involved in the regulation of food intake and the sleep-wake cycle, is decreased in OSA patients.62-64 In a study conducted by Aksu et al,62 the relationship between OSA, cigarette smoking and plasma orexin-A was investigated. The authors found there was no significant difference between never smokers and ex/current smokers in plasma orexin-A levels in non-OSA subjects, while in the OSA sub-group, plasma orexin-A levels were significantly lower in never smokers than in ex/current smokers. The results implied that smoking might affect orexin-A levels in OSA patients.
SLEEP APNEA: A PREDISPOSING FACTOR FOR NICOTINE ADDICTION?
A provocative hypothesis was formulated in early 1990s by Wetter et al7 and Schrand12 that smoking may represent as a form of self-treatment in patients with OSA. Patients with OSA has presented with symptoms of hypersomnolence, depression and cognitive dysfunction. People with these symptoms are more likely to be incompetent in their work and be ostracized by their peers. Since nicotine has been shown to cope with these symptoms, patients with severe OSA may be encouraged to solve these social problems by smoking to maintain alertness. Thus among those untreated OSA patients with severe symptoms of depression and cognitive dysfunction, treating OSA may be a necessary precondition for smoking cessation.
As for addiction mechanism, the pleasure centers encourage the immediate continuance of activities which are necessary to the preservation of life.12 Long-term hypoxia has been found to increase the release of dopamine (DA) in the carotid body65 and nicotine would also increase DA levels in the brain. As mentoned above, nicotine has been shown to increase ventilation and decrease upper airway resistance.34-36 When there is long-term hypoxia and an act is associated with an increase in respiration and oxygenation, the pleasure centers would be stimulated and thus addiction and compulsive activity would be encouraged.12
The association between smoking and OSA is shown in Figure 1. The influence to respiratory system of smoking, the stimulant effects of nicotine and nightly nicotine withdrawal are the latent mechanisms for smoking as a pathogenic mechanism of OSA. This association is at least partly supported by the lack of increased risk for OSA in former smokers after an adequate period of smoking cessation. Of note, smoking may join with OSA in a common pathway to increase the risk for systematic injury like CVD. OSA, in turn, may be responsible for nicotine addiction. Thus, on one hand, smoking cessation is recommended when considering treatment for OSA, while, on other hand, treating OSA may be a necessary precondition for smoking cessation, especially amongst those untreated OSA patients with severe symptoms such as daytime sleepiness, depression and cognitive dysfunction.
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