Chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema, is characterized by progressive, not fully reversible, airflow limitation resulting from injury to the small airways and alveoli from noxious particles or gases. Patients typically present with dyspnea and/or chronic cough. Sleep-related complaints are common and include repetitive awakenings, insomnia, nonrestorative sleep, and excessive sleepiness (1,2). Polysomnography (PSG) may demonstrate prolongation of sleep onset latency (SOL), decrease in sleep efficiency (SE), reduction in total sleep time (TST) and greater frequency of arousals and awakenings, or may be entirely normal (3, 4, 5 and 6).

Insomnia is common among patients with COPD. In one study involving 50 subjects with emphysema, 72% reported having daytime sleepiness and 32% had impaired cognition (7). In the Tucson Epidemiologic Study of Chronic Lung Disease, more than 50% of subjects with COPD had insomnia, and the prevalence of insomnia varied depending on the presence and number of symptoms (cough or wheezing)—28% for asymptomatic patients, and 39% and 53% for those with one symptom or two symptoms, respectively (8).

The cause of sleep disturbance in patients with COPD is often multifactorial, and may involve nocturnal coughing, wheezing, dyspnea, or orthopnea; increased work of breathing; and medication use, including methylxanthines, beta-adrenergic agonists, anticholinergic agents, and systemic corticosteroids (9, 10, 11, 12, 13 and 14). Patients with advanced COPD may develop sleep-related hypoxemia and hypercapnia, but the frequency of arousals in this population does not appear to be related to the degree of nighttime hypoxemia (15). Finally, both restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) may also disrupt sleep in patients with COPD (16,17).

Sleep-related oxygen (O₂) desaturation can develop in patients with moderate to severe disease, in whom episodes of O₂ desaturation are more frequent, of greater duration, and more severe during rapid eye movement (REM) sleep. Nocturnal
hypoxemia is also more common in patients with chronic bronchitis compared to those with emphysema. In COPD, sleep-related hypoxemia may result from hypoventilation (most important mechanism), ventilation-perfusion (V/Q) mismatching, or decrease in lung volumes.

The term “overlap syndrome” is defined by the presence of both COPD and obstructive sleep apnea (OSA). Compared to isolated COPD, this disorder is associated with lower partial pressure of oxygen (PaO₂), higher partial pressure of carbon dioxide (PaCO₂), and higher mean pulmonary artery (PA) pressures. Polysomnography is not routinely indicated in persons with COPD, but should be considered if there is a clinical suspicion for OSA, if complications from unexplained hypoxemia are present, or if the severity of pulmonary hypertension is out of proportion to the degree of airflow limitation (18).

Therapy for nocturnal symptoms related to COPD consists of long-acting beta-agonists (e.g., salmeterol), theophylline and long-acting anticholinergic agents (e.g., tiotropium). Oxygen therapy should be considered for patients with significant nocturnal O₂ desaturation (3,4). Positive airway pressure (PAP) therapy is indicated for patients with the overlap syndrome. Finally, lung volume reduction surgery (LVRS) has been shown to improve sleep duration and quality; however, the mechanism for improved sleep quality following LVRS is unknown, and does not appear to be due to improved nocturnal oxygenation (6).

In asthma, airway hyperreactivity to specific and nonspecific stimuli gives rise to reversible bronchoconstriction, and episodic dyspnea, wheezing or coughing. About three-fourths of patients with asthma report nocturnal awakenings occurring at least once weekly, and two-thirds have nocturnal awakenings occurring three times or more a week (19). Poor sleep quality and frequent arousals are due principally to coughing, dyspnea, wheezing, and chest discomfort. Patients may also develop insomnia or excessive sleepiness, and nocturnal hypoxemia. Several mechanisms may explain the worsening of asthma symptoms during the night (20,21). There is an observable circadian variability in airflow, with lowest levels in the early morning. In addition, sleep-related changes in autonomic nervous system activity (i.e., increase in parasympathetic tone and decrease in sympathetic activity), lung capacity, and inflammatory mediators may alter both bronchoreactivity and airway lumen size (22). Lastly, nocturnal asthma may be exacerbated by nocturnal gastroesophageal reflux (GER) or OSA (23).

Diagnosis of nocturnal asthma requires monitoring morning and evening peak expiratory flow rate (PEF) or forced expiratory volume in 1 second (FEV₁) over several days to weeks; both may show reduced values in the evening compared to the daytime.

Therapy of nocturnal asthma consists of optimal use of inhaled corticosteroids and long-acting bronchodilators (e.g., salmeterol) (24). Short-acting betaagonists (e.g., albuterol) are used for acute control. Positive airway pressure therapy may help reduce symptoms in certain patients with concurrent asthma and OSA.

The prevalence of sleep-related breathing disorders (SRBD), including OSA, central sleep apnea (CSA), and Cheyne-Stokes respiration (CSR; waxing and waning breathing pattern followed by periods of apneas) is increased in patients with heart failure (HF). Obstructive sleep apnea and CSA may coexist in these patients.

In several recent large studies, OSA was noted in 20% to 30% of overweight patients with systolic HF (25, 26, 27 and 28). Left ventricular (LV) systolic dysfunction is an independent risk factor for OSA in this population. Conversely, untreated OSA may
contribute to worsening LV dysfunction and higher mortality in some, but not all, patients. Mortality is increased in CHF persons with worse apnea hypopnea indices (AHI) and increased left atrial sizes (29,30). Continuous positive airway pressure (CPAP) therapy in patients with OSA and HF have demonstrated improvements in LV ejection fraction, daytime blood pressure (BP), heart rate (HR), and urinary catecholamine excretion (31,32).

It is estimated that CSR is present in 30% to 40% of HF patients (25, 26 and 27). Mortality is also greater in patients with HF who develop CSR compared to those without CSR. Nonetheless, it is unclear if CSR is simply a harmless clinical feature of HF, or whether it increases the progression of heart disease and risk of death (33). One study noted that the presence of CSA, severity of right ventricular (RV) systolic dysfunction, and low diastolic BP correlated with poorer survival in patients with systolic HF. The negative impact of CSA on survival persisted even after adjusting for other potential confounders, including LV ejection fraction and New York Heart Association (NYHA) functional status (34). Optimizing medical treatment should be the first step in addressing the presence of CSA-CSR in patients with HF. If CSA persists, specific treatment options include nocturnal supplemental O₂ therapy, theophylline, acetazolamide, atrial overdrive pacing, cardiac resynchronization therapy, and PAP therapy. Continuous positive airway pressure therapy in patients with HF and OSA improves LV systolic function and quality of life (QOL), and may improve prognosis. A large randomized multicenter trial of 258 patients with HF receiving optimal medical therapy investigated if long-term treatment of CSA with CPAP reduced rates of death and heart transplantation. The study was terminated early due to increased early mortality in the CPAP group. After a mean follow-up period of 2 years, CPAP therapy significantly increased LV ejection fraction and 6-minute walking distance but did not alter heart transplant-free survival (35). A post-hoc analysis of the study revealed that survival was significantly better in patients in whom CSA was effectively controlled compared to controls (36). Possible adverse hemodynamic effects of CPAP in HF patients include reduction in venous return and decrease in RV systolic function due to elevated intrathoracic pressures.

Sleep-related breathing disorders, including OSA and CSA, may also be common in patients with diastolic HF, and their prevalence appears to be related to the severity of impairment of diastolic function (37). In this group, CPAP therapy has been demonstrated to improve echocardiographic indices of diastolic function (38).

Cyclic variability in HR, with reductions associated with apneas and increases during hyperpneas, is frequently noted in OSA (39).

The risk of IHD is increased in middle-aged persons with OSA. This increased risk is independent of age, BMI, BP and smoking history, and is reduced by reversal of OSA (46, 47 and 48). In the SHHS, 16% of patients with OSA described having at least one manifestation of cardiovascular disorder, such as myocardial infarction, angina, coronary revascularization procedure, HF or stroke (46). In a prospective cohort of 408 patients with IHD who were followed for a median period of 5 years, those with an AHI of ≥10 had a 62% relative increase and a 10.1% absolute increase in the composite endpoint of death, cerebrovascular events, and myocardial infarction (49).

Possible mechanisms for the greater prevalence of IHD in patients with OSA include endothelial dysfunction; hypercoagulable state (increased plasma fibrinogen levels, increased platelet activity, and decreased fibrinolytic capacity); insulin resistance; increase in proinflammatory cytokines (TNF-α, IL-6 and IL-8) and adhesion molecules; greater stress; heightened sympathetic activity during arousals from sleep; and marked sleep-related hypotension (particularly during stage N3 sleep).

Effective CPAP therapy can reduce both fatal cardiovascular events (i.e., death from myocardial infarction or stroke) and nonfatal cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, coronary artery bypass surgery, and percutaneous transluminal coronary angiography, in persons with OSA (50).

Patients with OSA may have altered circadian rhythms of cardiac ischemic events and sudden cardiac deaths compared to those without OSA. Patients with myocardial infarctions occurring between midnight and 6 AM have a greater likelihood of having OSA (51). The risk of sudden death from cardiac causes peaks from 6 AM to noon, with a nadir from midnight to 6 AM in the general population. In contrast, sudden death from cardiac causes mostly occurs between midnight and 6 AM among patients with OSA (52). In summary, the timing of sudden cardiac deaths appears to be affected by the presence OSA but it is not known if the latter increases the risk (33).

Obstructive sleep apnea is a known risk factor for hypertension independent of known confounding factors (53, 54 and 55). In the seventh report of the Joint National Committee on the prevention, detection, evaluation and treatment of high blood pressure, OSA is listed as an identifiable cause of hypertension (56). In the Wisconsin Sleep Cohort Study, the odds ratios for the presence of hypertension at 4 years follow-up (relative to an AHI of 0 events per hour at baseline) were 1.42, 2.03, and 2.89 with baseline AHI of 0.1 to 4.9, 5.0 to 14.9, and 15.0 or more events per hour, respectively (53).

Not all investigators have noted this association. In the SHHS, AHI was not a significant predictor of future hypertension at 5 years follow-up among middleaged and older patients without hypertension after adjusting for BMI (54).

Obstructive sleep apnea increases both systolic and diastolic BP as well as the prevalence of hypertension. There can be a loss of the nocturnal fall in BP (“dipping” phenomenon), and the risk of CVD may be greater among “nondippers” compared to “dippers.” Blood pressure control improves during PAP therapy in persons with OSA and hypertension, the benefits being larger in patients with more severe OSA, excessive daytime sleepiness or difficult to control hypertension; in those taking antihypertensive agents; and in patients with better CPAP compliance. A metaanalysis of randomized controlled trials from 1980 to 2006 evaluating the effects of CPAP on BP in patients with OSA reported a mean net change in systolic BP of −2.46 mm Hg, diastolic BP of −1.83 mm Hg, and mean arterial pressure of −2.2 mm Hg compared to controls (55).

Recurrent episodes of nocturnal hypoxia related to OSA can lead to pulmonary capillary vasoconstriction and, subsequently, to sustained pulmonary hypertension. The prevalence of pulmonary hypertension in patients with OSA but no associated cardiopulmonary disease is about 20% (57, 58 and 59), and the severity of the pulmonary hypertension in these patients is generally mild. In one randomized controlled crossover study, CPAP therapy for 12 weeks was effective in lowering pulmonary artery systolic pressure in patients with severe OSA and pulmonary hypertension (60). Nevertheless, neither the clinical significance nor long-term consequences of pulmonary hypertension in patients with OSA are completely understood (61).

In this disorder incompetent barriers at the gastroesophageal junction, including transient relaxation of the lower esophageal sphincter (LES), produces backflow of gastric contents and acid to the esophagus. Recent prevalence estimates suggest that 45% to 54% of patients with GER have nighttime symptoms, and sleep impairment is frequently reported by these patients (62, 63, 64, 65 and 66). More importantly, patients with nocturnal GER have more severe symptoms, higher prevalence of atypical manifestations, and greater work loss compared to those with primarily daytime symptoms (66, 67 and 68). Nocturnal GER is associated with prolonged SOL and more frequent awakenings (69).

During sleep, GER occurs mainly during brief arousals (70). Patients awakening from sleep may experience heartburn, dyspnea, coughing or choking, retrosternal chest pain, or a bitter or sour taste. Compared to events that occur during the waking state, sleep-related GER is associated with longer acid contact time because of delayed esophageal acid clearance and decreased production of neutralizing saliva. The likelihood of sleep-related GER increases with aging and, perhaps, with OSA. If significant, GER can result in various gastrointestinal (i.e., esophagitis, esophageal strictures, and Barrett esophagus) and respiratory (i.e., chronic cough, asthma exacerbation, pharyngitis, laryngitis, bronchitis, pneumonia, and pulmonary fibrosis) complications. In a study investigating potential risk factors among patients with difficult-to-treat asthma, the presence of GER was associated with frequent asthma exacerbations (71). There is a significant correlation between spontaneous episodes of GER and bronchoconstriction, and the severity and duration of the latter was related to reflux duration (72). Lastly, GER is also associated with sleep-related bruxism (73).

Since obesity is a confounding factor for both GER and OSA, patients often present with both conditions (74). In a large European cross-sectional survey, the
presence of GER was associated with daytime sleepiness, daytime tiredness, and disrupted breathing (75). While patients with OSA may have a higher prevalence of GER (76), there is no evidence supporting a causal relationship between nocturnal heartburn and OSA (65,77).

Diagnosis of GER relies on a compatible clinical history, and can be aided by esophageal pH testing during PSG. It is useful to correlate episodes of GER with respiratory events and arousals. With esophageal pH testing, the pH probe is placed 5 cm above the LES, and GER events are reported when pH drops below 4 (74). Placement of a wireless pH-monitoring capsule may be better tolerated than conventional 24-hour pH monitoring (78,79), but currently lacks integration with PSG (80). In a recent investigation, actigraphy was used to monitor differences in reflux activity during recumbent-awake and recumbent-asleep states (81,82).

Therapy of sleep-related GER consists of lifestyle modification, use of medications (H2 antagonists or proton pump inhibitors), or antireflux surgery. Positive airway pressure therapy may benefit patients with concurrent OSA.

Lifestyle modifications include optimal weight management and positional therapy, such as elevating the head of bed or sleeping in a left lateral decubitus position (83, 84 and 85). Certain medications, including benzodiazepine receptor agonists, can aggravate nocturnal GER; these should be discontinued if clinically appropriate (86, 87 and 88).

Pharmacologic therapy for sleep-related GER symptoms includes the use of antacids for acute symptoms, and H2 antagonists or proton pump inhibitors (PPI) to reduce gastric acid secretion (81,89, 90, 91 and 92). Promotility medications, such as metoclopramide and bethanechol, have also been used to improve esophagogastric motility, LES competence, gastric emptying and esophageal clearance, but their use is limited by central nervous system adverse effects (93).

Nissen fundoplication has been shown to alleviate nocturnal heartburn and associated sleep disturbances (65), and may be more effective than maintenance PPI agents (94,95). Proper patient selection is important (96). Gastric bypass surgery may be considered in morbidly obese patients, in whom it can decrease both heartburn symptoms and objective acid reflux with the additional benefits of weight loss (97).

Finally, CPAP therapy has salutary effects in patients with OSA and GER. In this population, it has been shown to improve nocturnal GER symptoms by 48%, with an inverse direct correlation between increasing CPAP pressure and improvements in GER symptoms (65,74).

Sleeping sickness, or Human African trypanosomiasis (HAT), is caused by infection with Trypanosoma brucei gambiense or T.b. rhodesiense, and transmitted by the bite of an infected tsetse fly. Human infection is endemic in certain regions of intertropical Africa, and consists of two stages, namely an initial hemolymphatic stage, characterized by fever, cervical adenopathy and cardiac arrhythmias, and a terminal meningo-encephalitic stage, with progressive hypersomnolence, sensory deficits, abnormal reflexes, altered consciousness, cachexia, coma and eventual death. Complaints of insomnia are not uncommon and reversal of sleep-wake periods may occur. Cerebrospinal fluid hypocretin-1 levels in patients with differing stages of HAT are higher than in patients with narcolepsy-cataplexy (98). Polysomnography performed in infected persons may demonstrate a paucity of vertex sharp waves, sleep spindles, and K complexes as well as shortened REM sleep latency or sleep-onset REM periods (SOREMPs). Deregulation of the 24-hour sleep-wake pattern may be present (99). Diagnosis requires the demonstration of the offending pathogens in blood, bone marrow, lymph node aspirates, or cerebrospinal fluid.

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