Sleep in COPD Patients

Abstract

An estimated 14 million Americans are afflicted with COPD and are at risk for significant abnormalities in gas exchange and ventilation that are exacerbated by sleep. In addition 10–15% of COPD patients concomitantly suffer from sleep apnea. The term “Overlap Syndrome” was originally coined by Flenley to describe the relationship between COPD and sleep apnea. Patients with overlap syndrome are characterized by having lower PaO₂ during wakefulness, higher PaCO₂, elevated pulmonary artery pressure and more significant episodes of nocturnal hypoxemia than sleep apnea patients without COPD. COPD and sleep apnea have long been individually recognized for having significantly detrimental affects on the respiratory physiology of patients. The mechanisms of both diseases compromise the gas exchange, oxygenation, and overall mortality and morbidity in the affected patients. While both of these diseases individually represent significant detriment to affected patients, the combination of these two diseases has been shown to have an even more profound affect on patients' oxygenation, gas exchange, and breathing patterns. As our understanding of the physiological processes of sleep develops, the relationship between obstructive sleep apnea and obstructive lung disease has become progressively more apparent. Identification and appropriate management of these patients is particularly important because the 5 year survival of patients with overlap syndrome is lower than that of patients with sleep apnea alone as shown in prospective trials.

Key words: :

• Hypoxemia
• Hypoventilation
• Polysomnography
• Apnea
• Respiratory mechanics
• Overlap syndrome

Introduction

COPD and sleep apnea have long been individually recognized for having significantly detrimental affects on the respiratory physiology of patients. The mechanisms of both diseases compromise the gas exchange, oxygenation and overall mortality and morbidity in the affected patients. While both of these diseases individually represent significant detriment to affected patients, the combination of these two diseases has been shown to have an even more devastating affect on patients' oxygenation, gas exchange, and breathing patterns. As our understanding of the physiological processes of sleep develops, the relationship between obstructive sleep apnea and obstructive lung disease has become progressively more apparent.

Hypoventilation, alterations in gas exchange and breathing patterns during sleep have all been noted to have a disproportionate impact on patients with obstructive airway disease and sleep apnea. The physiological mechanisms of damage to the respiratory systems in COPD and OSA work symbiotically to impair these patients' ability to oxygenate effectively. Because of the similarities in the mechanisms of injury in these two disease processes, the combination of COPD and sleep apnea has been shown to have particularly devastating effects to the oxygenation and the efficiency of gas exchange. Nocturnal hypoxemia and gas exchange abnormalities have been recognized as some of the most significant causes of mortality and morbidity in COPD.

Even in normal individuals, sleep reduces effectiveness of the chemical, mechanical and cortical receptors in the respiratory centers. Additionally, normal sleep is associated with mild nocturnal bronchoconstriction, diminished rib cage and muscular contribution to respiratory effort and impairment of FRC. While the normal physiologic changes of sleep result in only minimal degrees of hypoventilation, hypercapnia, and respiratory depression in healthy patients, these physiologic changes of sleep can cause exaggerated respiratory impairment in COPD patients [1].

Frequent awakenings, worsening nocturnal airflow obstruction and nocturnal hypoxemia are some of the many causes for poorer sleep quality in COPD patients [1-3]. Respiratory issues, such as coughing, wheezing and dyspnea, cause increased episodes of disruption during sleep, reductions in REM and slow wave sleep and an overall poorer quality of sleep [1-3]. Studies have shown that symptom control in COPD patients may play a crucial role in maintaining their sleep hygiene.

A study performed at the Tucson Epidemiologic Study of Chronic Lung Disease showed that asymptomatic COPD patients reported significantly less insomnia than COPD patients with even one symptom (28% and 39.1% respectively) [4]. Daytime somnolence was noted to be 9.4% in asymptomatic COPD patients, 12.4% in COPD patients with one symptom and 22.8% in patients with two or more symptoms [4]. Patients with FEV₁/FVC ratios of less than 65% have been demonstrated to be at significantly increased risk of nocturnal hypoxemia [1]. In addition to inadequately compensating for the normal respiratory effects of sleep, COPD patients experience worse sleep quality and inhibited gas exchange. These changes in sleep lead to significant nocturnal hypoxia, contributing to increased mortality and morbidity in COPD patients. When these effects are compounded by the serious and potentially life-threatening effects of sleep apnea, COPD patients are at increased risk. Those caring for patients with COPD can optimize the care of these patients by aggressive screening, evaluation, and management of coexisting sleep-disordered breathing.

Effects of Sleep on Respiration in COPD

In order to fully appreciate the relationship between COPD and sleep apnea, it is important to understand the effects of sleep on breathing and ventilation/perfusion relationships (see Figure 1). Sleep has multiple effects on breathing, causing changes in the respiratory center function, bronchial airflow and muscular contribution to respiratory effort. Diminished effectiveness of the chemical, mechanical and cortical receptors on the respiratory center during sleep cause diminished minute ventilation during all stages of sleep, but are particularly influential during REM. This change in ventilation has been linked to rises in end-tidal PCO₂, particularly in patients with baseline respiratory insufficiency [5]. Nocturnal bronchoconstriction has been a well-demonstrated phenomenon during circadian changes in normal patients. The bronchoconstriction has been shown to be even more profound in patients with asthma, and may contribute to “morning dipping.”

Figure 1 The multiple effects of sleep on normal breathing.

Sleep has also been associated with significant reductions on intercostal muscle activity causing impairments of the anatomic accessory muscle contribution to ventilation. COPD patients tend to experience worsening airflow obstruction during sleep, particularly in the early morning [2]. Airflow obstruction typically worsens in the early morning hours similar to asthmatics. While all people undergo certain physiologic changes during sleep, the affects of sleep tend to be accentuated in COPD patients, leading to more severe nocturnal hypoxia and its multiple effects on respiration.

Nocturnal Hypoxemia

Nocturnal hypoxia (?) has been identified as one of the major mechanisms of injury experienced by patients who suffer from the Overlap Syndrome, causing multiple adverse effects. These include poor sleep quality, pulmonary hypertension, and overall higher morbidity and mortality. While the primary mechanism for hypoxemia is felt to be the physiologic hypoventilation that occurs during normal sleep [6], hypoventilation, changes in the oxyhemoglobin dissociation curve, decreased FRC and modifications in the ventilation/perfusion relationships are mechanisms that further impair nocturnal oxygenation in COPD patients [7].

In healthy wakeful subjects, ventilation has been shown to decrease by 10–15% during NREM sleep [8], and this effect is even more pronounced during REM sleep. Minute ventilation has been shown to fall as much as 25% between wakefulness and NREM sleep in hypercapneic COPD patients [9]. Reduced daytime SaO₂ < or = 93% in COPD patients has been identified as a significant clinical predictor of nocturnal hypoxemia [10]. Patients with obstructive airway disease tend to have a diminished ventilatory response to the CO₂ retention and hypoxemia caused by nocturnal alveolar hypoventilation. COPD patients experience the same 8–10 mm Hg drop in overnight PO₂ levels as patients without COPD. This change in PO₂ leads to significant hypoxemia in COPD patients, particularly in COPD patients who have lower daytime PO₂ levels. The lower baseline PO₂ levels cause COPD patients to be particularly sensitive to these nocturnal changes in PO₂ [2][7].

The most clinically significant problems associated with “Overlap Syndrome” directly result from nocturnal oxygen deprivation. A variety of deleterious cardiac, hematologic, and neurological effects can be directly related to hypoxemia. These effects include cardiac dysrhythmias (i.e., ventricular ectopy), elevations of pulmonary artery pressure and polycythemia. Nocturnal hypoxemia has been independently associated with reduced survival and impaired sleep quality and even nocturnal death [11].

Gas Exchange

Both sleep and COPD disrupt the normal ventilation/perfusion relationship in different ways. Hypoventilation, decreases in FRC, and increased airflow obstruction occur routinely during normal sleep resulting in modest ventilation/perfusion abnormalities. COPD is associated with increased airflow resistance, insufficient ventilatory response and increased pulmonary dead space [11]. Reduced intercostal muscle activity during sleep tends to diminish an already impaired FRC in some patients with COPD [6]. The further reduction in FRC creates a worsened ventilation/perfusion relationship and further contributes to the nocturnal hypoxemia. These various mechanisms contribute to hypoxia and are especially devastating to a patient with baseline respiratory insufficiency.

During sleep, COPD patients experience an exaggeration of the changes in PCO₂ and CO₂ chemoresponsiveness that occur during sleep in normal individuals. The decrease in ventilation and ventilatory response to CO₂ is proportional to the depth of sleep. As patients enter the deeper phases of sleep, the arterial PCO₂ rises. COPD patients tend to have a more significant response to these normal physiologic changes of sleep due to their lower daytime and nocturnal PO₂ values. These lower PO₂ values tend to place these patients on the steeper slope of the oxygen/hemoglobin dissociation curve. This unique physiology in COPD patients predisposes them to significant nocturnal hypoxemia.

Indications for Sleep Evaluation in COPD Patients

While testing for sleep apnea in COPD patients is not routinely recommended, early recognition and management may help avoid the potentially life-threatening complications of nocturnal hypoxemia. COPD patients should be carefully screened for signs and symptoms of sleep apnea with a careful history and physical.

Clinical Presentation of SDB

Habitual snoring is the most common symptom in patients with SDB, but the majority of people who snore do not have sleep apnea. Snoring accompanied by witnessed apneas [12&13]. Excessive daytime sleepiness, while not specific, should increase the suspicion for OSA. Subjective sleepiness may be assessed by use of the Epworth Sleepiness Scale (Table 1), which has been validated in clinical studies and correlates roughly with objective measures of sleepiness [14]. Patients both under and over report their own sleepiness, so querying their significant others may also be useful. An Epworth score greater than 10 suggests significant daytime sleepiness, although it is not specific for OSAS. Patients who report falling asleep while driving should be evaluated for sleep disorders including SDB. Many sleep problems may result in falling asleep while driving, including sleep deprivation. However, because of the threat this symptom poses to the patient and to others, clinicians should have a low threshold to refer sleepy drivers to a sleep center for thorough evaluation. A history of hypertension should also increase the clinician's suspicion for OSAS. Hypertension is an independent risk factor for sleep apnea, and the prevalence of sleep apnea is particularly high in patients with drug-resistant hypertension [15&16].

Table 1.  The Epworth Sleepiness Scale

How likely are you to doze off or fall asleep in the following situations, in contrast to just feeling tired? This refers to your usual way of life in recent times. Even if you have not done some of these things recently, try to work out how they would have affected you. Use the following scale to choose the most appropriate number for each situation:
0 = would never doze
1 = slight chance of dozing
2 = moderate chance of dozing
3 = high chance of dozing
Situation	Chance of Dozing
Sitting and reading	_____
Watching TV	_____
Sitting, inactive, in a public place	_____
As a passenger in a car for an hour	_____
Lying down in the afternoon	_____
Sitting and talking to someone	_____
Sitting quietly after a lunch without alcohol	_____
In a car, while stopped for a few minutes in traffic	_____

The physical finding that is most predictive of OSAS is central obesity. A Body Mass Index (BMI) of 28 kg/m² in both men and women should increase the suspicion for OSAS. Roughly 40% of those with a BMI over 40 and 50% of those with a BMI over 50 have significant sleep-disordered breathing [17]. Measures of central obesity such as neck size are very useful in predicting the presence of OSAS. Men with a neck size of 17 inches (43 cm) or greater and women with a neck size of 16 inches (41 cm) or greater are very likely to have OSAS confirmed by overnight polysomnography [18]. The Berlin Questionnaire is a global diagnostic tool which allows patients to self-report on a list of signs and symptoms frequently associated with OSA. The Berlin Questionnaire contains questions regarding OSA risk factors, height, weight, daytime sleepiness, drowsy driving and the presence and frequency of snoring and witnessed apneas [19].

Clinical signs of persistent hypoxemia are also important signals to consider in sleep apnea. The presence of polycythemia, cor pulmonale and neuropsychiatric problems in patients with daytime PaCO₂ > 60 mm Hg may indicate the need for further evaluation of sleep apnea [7]. Because of the potentially devastating effects of Overlap Syndrome, screening for sleep apnea should be performed in all patients with obstructive lung diseases with a relatively low threshold to pursue diagnostic testing. Patients with strong clinical suspicion of overlap syndrome or manifestations of hypoxemia that are unrelated to awake oxygenation should be considered for polysomnography [20].

Diagnostic Testing

Assessing the presence and degree of nocturnal hypoxemia is often evaluated by sleep monitoring equipment such as pulse oximetry [21]. It is important to note that current sleep monitoring equipment may underestimate the degree of nocturnal hypoxemia [21]. Another caveat to home oxygen pulse oximetry is the significant night-to-night variability of the oxygen desaturation in COPD patients [18]. A recent study showed inter-night variability that was so profound it would have changed the clinical decisions made in over 33% of the patients studied [18]. Studies examining the diagnostic acumen of overnight pulse oximetry have all demonstrated the importance of repeated nighttime measurements to ensure appropriate diagnosis [18][21].

Monitoring conditions may disrupt the normal sleep architecture, causing increased wakefulness and, consequently, fewer episodes of REM sleep and hypoxemic episodes [21]. This information demonstrates that hypoxemic episodes may be missed or significantly underestimated in COPD patients. Therefore, if clinical suspicion of sleep apnea is high and/or the patient is at high risk for developing adverse effects from the hypoxemia, polysomnography should be seriously considered.

In summary, a thoughtful history and sleepiness scoring for COPD patients are effective and important screening tools to aid in the recognition of patients with Overlap Syndrome. Once clinical suspicion has been established, polysomnography and overnight pulse oximetry are useful tools for confirming the diagnosis.

Management

The management strategies for patients with Overlap Syndrome is comprised of four essential components: appropriate COPD management, supplemental oxygen, pharmacologic therapy and NIPPV.

General Measures

General measures, such as smoking cessation, immunizations, and appropriate and timely management of exacerbations are an important foundation to the management of these patients. Taking the appropriate measures for all COPD patients is a simple but essential component of dealing with patients with Overlap Syndrome [5]. The importance of smoking cessation is a crucial aspect of therapy and its importance in treatment cannot be overemphasized. There is evidence that smoking is an independent risk factor for sleep apnea [22], and also for poor sleep [23]. In addition, it is the only intervention that slows the decay of COPD [24&25].

Pharmacological Therapy

Another important goal of managing patients with concurrent COPD and sleep apnea is to optimize the COPD regimen with bronchodilators and anticholinergic therapies [5]. In a randomized, double-blind, placebo-controlled study of severe stable COPD patients, long-acting anticholinergic therapy was shown to significantly improve nocturnal oxygen saturation without adversely affecting sleep quality [6]. The patients treated with long-acting anticholinergic therapy demonstrated improvements in SaO₂ of 2.41% during REM and 2.49–3.06% during total sleep time [6]. Anticholinergic medications help to decrease airflow obstruction and may have a inhibiting the effects of elevated cholinergic tone overnight [6].

Supplemental Oxygen Therapy

Most of the deleterious effects of untreated sleep apnea in COPD patients can be directly related to desaturation, therefore oxygen therapy is a crucial component in the management of these patients. Hypoventilation has been identified as a significant component to nocturnal desaturations in COPD patients [26]. These episodes of nocturnal desaturations improve with the use of supplemental oxygen [27]. Approximately half of patients on long term oxygen therapy require an additional 1 L/min during sleep [27]. A study conducted by Cuvelier [26], demonstrated that the Demand Oxygen Delivery System (DODS) was as effective as oxygen alone with significant oxygen savings [26]. This system is thought to be an effective method of conserving oxygen, reducing costs and improving patient autonomy [26].

The severity of hypoxemia has been directly linked with the presence and degree of complications, such as arrhythmias, pulmonary hypertension, and polycythemia. Supplemental oxygen therapy has been found to have significant beneficial impacts in the clinical course of pulmonary hypertension [21]. While supplemental oxygen therapy has been shown to effectively improve nocturnal hypoxemia and its consequences, interestingly, it has not yet been shown to improve sleep quality [6].

NIPPV

While providing supplemental oxygen is very effective, some patients will require additional respiratory support with non-invasive ventilation to compensate for the hypoventilation from respiratory muscle insufficiency [28]. While NIPPV, particularly CPAP, has been found to be helpful in compensating for alveolar ventilation, the evidence regarding its helpfulness in treating gas exchange, work of breathing, and symptoms of dyspnea is somewhat less compelling. Despite these findings, the consensus conference on NIPPV proposed that “1) improvements in gas exchange, 2) stabilization of slowly or nonprogressive processes that have adversely affected respiratory mechanics, and 3) the alleviation of symptoms of hypoventilation” [28] occur with intermittent long term ventilation. Even CPAP alone (without oxygen) has been found to be effective in patients by maintaining the patency of the upper airway. Most studies using non-invasive positive pressure ventilation for patients with severe COPD have found significantly favorable effects on sleep such as reduction in daytime PaCO₂, improved sleep quality and likely increased respiratory drive [28].

Conclusion/Discussion

As our understanding of the physiological processes of sleep develops, the relationship between obstructive sleep apnea and obstructive lung disease has become progressively more apparent. One study showed evidence of concomitant COPD in up to 28% of CPAP dependant OSA patients [29]. While OSA and COPD both represent significant clinical entities independently, it is important to recognize that the combination of these two disease states results in an even more significant clinical problem for affected patients. This phenomenon (known as the Overlap Syndrome) has been well documented in the medical literature as having significant detrimental affects on the respiratory physiology of patients.

The combination of COPD and sleep apnea causes significant compromises in the gas exchange, oxygenation, and overall mortality and morbidity in the affected patients. The normal respiratory changes of sleep, such as hypoventilation, alterations in gas exchange, and breathing patterns tend to be exaggerated by the presence of obstructive airway disease and sleep apnea. Nocturnal hypoxemia and gas exchange abnormalities have been recognized as one of the most significant causes of mortality and morbidity in COPD [30]. Because of the additive detrimental affects of COPD and sleep apnea on patients, it is extremely important to identify these patients early and treat them aggressively.

Early recognition of patients with Overlap Syndrome is critical to avoid the complications of nocturnal hypoxemia. Thorough history and physical examinations combined with nocturnal pulse oximetry or polysomnography are extremely useful in diagnosing patients with Overlap Syndrome. Once a patient has been diagnosed, aggressive and timely management is crucial to help avoid the long-term complications of hypoxemia. The four cornerstones of therapy (see Figure 2) include a combination of general measures (i.e., smoking cessation), pharmacologic therapy, supplemental oxygen and NIPPV.

Figure 2 Overlap syndrome management.

In conclusion, the combination COPD and sleep apnea (i.e., Overlap Syndrome) has a profound affect on patients' oxygenation, gas exchange, and breathing patterns. Identification and appropriate management of these patients is particularly important because, as shown in prospective trials, the 5 year survival of patients with Overlap Syndrome is lower than that of patients with sleep apnea alone [7].