Chronic Obstructive Pulmonary Disease Gas Exchange During Sleep

Recurrent episodes of nocturnal arterial oxyhemoglobin desaturation, especially during rapid eye movement (REM) sleep, have been extensively described in patients with COPD (1-3). Several definitions of nocturnal desaturations have been proposed:

1. 30% of sleep time with oxygen saturation < 90% (4,5).

2. > 5 minute of sleep time spent with oxygen saturation below 90% and a nadir value < 85%, mostly during REM sleep (3).

3. Mean nocturnal SaO2 < 90% or the time spent with an SaO2 < 90% (6).

All patients with COPD are more hypoxemic during sleep than during a resting awake state. Generally, the patients who are most hypoxemic while awake are the ones most severely hypoxemic during sleep but the degree of nocturnal desaturation differs markedly among COPD patients (1,2,7-9). Results of pulmonary function tests correlate poorly with nocturnal hypoxemia, since this latter may be affected by comorbid conditions, such as heart failure and obstructive sleep apnea (OSA); however, the drop in oxygen saturation during sleep is higher than that observed during maximal exercise (10).

Sleep-related oxyhemoglobin desaturation generally occurs during REM sleep but is not specific to this sleep state. Indeed, desaturations may occur during non-REM (NREM) sleep, particularly during stages 1 and 2, but in this context their amplitude is generally less pronounced and their duration limited to a few minutes. There is a close relationship between the daytime and nocturnal level of PaO2: patients who are most hypoxemic when awake became more hypoxemic when asleep (11,12). This relationship is mainly due to the shape of the oxygen dissociation curve: a drop in PaO2 may have different consequences depending on the baseline level of SaO2. The amplitude of desaturation is very large when the baseline SaO2 is near or below the 90%.

Many of the physiological variables in COPD with nocturnal desaturation differ (13). A study published in 2005 showed that the variables that best identify patients with desaturation are the percentage of time spent with SaO2 < 90% (T90), mean pulmonary arterial pressure, and PaCO2 values rather than the T90 alone (14).

Many studies were conducted to identify the best predictors of nocturnal SaO2 dips, so that patients at risk may receive an appropriate diagnostic examination. In particular, the problem regards those patients with daytime PaO2 > 8 kPa. Data obtained from different studies are summarized in Table 1 (3,6,13-15).

COPD was classified as a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases (16). Declining lung function over time is an important component in the natural history of this disease. Different populations, such as susceptible smokers, nonsus-ceptible smokers, nonsmokers, have different trends in their lung function decline over time. Impaired lung function is a strong predictor of morbidity and mortality. However, COPD is a heterogeneous disease so that patients may present different phenotypes (17): for example, people who have frequent exacerbations or people who lose lung function at a faster rate than the rest of the population (18).

The role that nocturnal desaturations play in the natural history of COPD is not well known. More attention has been paid to patients, whose awake arterial oxygen tension is above 60 mmHg, in other words, patients with mild or absent daytime hypoxemia. It has been suggested that nocturnal desaturations occurring in patients without significant daytime hypoxemia could lead to permanent pulmonary hypertension, precipitating the development of cor pulmonale. Fletcher et al. (19) demonstrated that patients with nocturnal desaturation had a lower survival rate than those without; they also found that "desaturators" treated with nocturnal oxygen supplementation tended to survive longer than those who were not treated, although the difference was not statistically significant. However, Chaouat et al. (5) did not confirm that patients who had desaturations had higher pulmonary arterial pressures. Two different studies investigating the survival of COPD patients receiving long-term oxygen therapy for moderate hypoxemia found that long-term oxygen therapy treatment did not improve survival in this kind of patient (20,21). Furthermore, a two-year follow-up study by Chaouat et al. (22) suggested that the presence of isolated nocturnal hypoxemia or sleep-related worsening of moderate daytime hypoxemia in COPD patients neither favors the development of pulmonary hypertension nor leads to a worsening of daytime blood gases. However, more recently, a prospective study with a follow-up of 42 months indicated that nocturnal desaturation may represent an independent risk factor for the development of chronic respiratory failure in COPD patients with a daytime PaO2 > 60 mmHg (23).

TABLE 1 Predictors of Nocturnal Hypoxemia in Patients with Chronic Obstructive Pulmonary Disease and Mild Daytime Hypoxemia

Predictors of nocturnal desaturation

Fletcher et al. (3) Lower PaO2 and higher PaCO2

Bradley et al. (13) Daytime hypercapnia

Vos et al. (6) Daytime PaO2, hypercapnic ventilatory response and sleepiness

Toraldo et al. (14) Mean pulmonary artery pressure, daytime PaCO2

This study, by Sergi et al., was conducted on 52 COPD patients with a stable daytime PaO2 above 60 mmHg, absence of clinical or ECG signs of cor pulmonale and absence of OSA (apnea-hypopnea index < 5 events/hour). The patients were subdivided at enrollment in two groups on the basis of presence of nocturnal desatura-tions. The authors observed that the onset of chronic respiratory failure was much more common in desaturators than among those who did not (Fig. 1). Three independent factors were associated with the onset of chronic respiratory failure: PaCO2, FEV1 (forced expiratory volume in 1 second), and nocturnal desaturation.

Finally, many studies focus on one fundamental point: nocturnal desatura-tions that worsen over time are present in patients who have a more rapid derangement of their lung mechanics, as demonstrated by a more rapid decline of FEV1, or a greater increase in PaCO2 (13,14,23,24).

The development of nocturnal desaturations in COPD patients has been attributed to several causes including changes in respiratory mechanics, worsening in ventilation/perfusion (V/Q) mismatch, increased airflow resistance, and progressive respiratory muscles weakness. Ballard et al. (25) found, in a group of COPD patients, that REM sleep caused a significant reduction in minute ventilation related to a decrease in tidal volume; increased resistances in the upper airway may contribute to this sleep-associated decrease in minute ventilation. During sleep there was a marked decrease in respiratory neuromuscular output, which fell by 39% during REM sleep. The authors concluded that sleep does not seem to alter lung volume or increase lower-airway resistance dramatically, but that a decrease in tidal volume and inspiratory flow are associated with increased upper airway resistance and reduced respiratory muscle activity. In another study, Becker et al. (26) investigated the mechanisms leading to hypoxemia during sleep in patients with various respiratory disorders including COPD. They found a more pronounced reduction in minute ventilation during REM sleep, irrespectively of the underlying disease, and concluded that reversal of hypoventilation during sleep should be a major therapeutic strategy for these patients. The work of breathing in COPD patients is already high while these patients are awake because of airways obstruction and

FIGURE 1 LTOT program enrollment curve in patient with (NOD) and without (n-NOD) nocturnal desaturations [see Ref. (23) for more details]. Source: S. Karger AG, Basel Editor.

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