Sleep Induced Hypoxemia in Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality worldwide. Sleep-induced hypoxemia is defined as “an SpO2 (oxyhemoglobin saturation) during sleep of < 90% for more than five minutes with a nadir of at least 85%” or “> 30% of total sleep time with an SpO2 of < 90%” in subject with a baseline awake SpO2 of ≥ 90%. Patients with moderate or severe COPD run a high risk of developing SIH mainly because of alveolar hypoventilation and ventilationperfusion mismatch. Compared to their non-SIH brethren, SIH COPD patients have greater degrees of pulmonary hypertension and cor pulmonale, require more frequent hospitalizations, and sustain higher mortality rates. And the necessity of treatment of isolated SIH in COPD has been debated for years. In this mini review, the definition, reasons, prevalence, clinical significance and treatment approaches of SIH in COPD are summarized. _______________________________________________________________________________________


INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation that is usually progressive and is a leading cause of morbidity and mortality worldwide. 1When pulmonary function deteriorates, and when the disease progresses, the risk of alveolar hypoxia and consequent hypoxemia in the patients with COPD increases.Hypoxia plays an important role in the progression of COPD and the extrapulmonary comorbidities.Previous studies found even patients with COPD with mild awake hypoxemia who did not qualify for home oxygen therapy had significant nocturnal desaturation.The phenomenon of nocturnal hypoxemia complicating COPD has been recognized for at least 50 years. 2Increased sleep latency, decreased total sleep time, decreased slowwave sleep, decreased rapid eye movement (REM) sleep, and the most important, sleep-induced hypoxemia (SIH), have been noted in many polysomnographic studies of patients with COPD. 3 SIH may predispose to pulmonary hypertension, cardiac arrhythmias during sleep and nocturnal death during exacerbations in patients with COPD.However, its importance and significance is not fully established.

Definition OF SIH
SIH in the ICSD-2 (The International Classification of Sleep Disorders: Diagnostic and Coding Manual) is defined as "an SpO 2 (oxyhemoglobin saturation) during sleep of < 90% for more than five minutes with a nadir of at least 85%" or "> 30% of total sleep time with an SpO 2 of < 90%" in subject with a baseline awake SpO 2 of ≥ 90%. 4,5

Reasons of SIH in COPD
Patients with COPD run a high risk of developing nocturnal hypoxemia. 6,7rst, SIH occurs in patients with COPD independent of any changes in upper airway mechanics for a number of factors, mainly including: airway obstruction, hyperinflation, respiratory muscle dysfunction, blunted ventilatory responses to hypoxia and ventilationperfusion mismatch.Alveolar hypoventilation, a normal feature during sleep, has a disproportionate effect on hypoxemic patients because of their position on the oxyhemoglobin dissociation curve, leading to significant nocturnal desaturation, even in patients with mild awake hypoxemia. 8 The second, arterial hypoxemia alone may be the product of worsening ventilation-perfusion mismatch with greater effective shunt. 5,10,11In addition, loss of accessory muscle activity during sleep especially REM sleep result in a decreased functional residual capacity (FRC) and a deterioration in pulmonary gas exchange, which leads to worsening ventilation-perfusion relationships and also aggravates nocturnal hypoxemia.
Alveolar hypoventilation occurs predominantly during REM sleep.Ventilation-perfusion mismatch can occur during non-REM sleep episodes as well. 6Overall, tidal volume and minute ventilation are decreased during REM, but the breathing pattern during REM sleep is irregular, with sudden changes in respiratory amplitude and frequency. 12

Prevalence and Clinical Characteristics of SIH in COPD
The prevalence of SIH among patients with COPD is unknown.Obviously, the lower the baseline SpO 2 in the population studied the higher the prevalence of SIH is likely to be.There is limited information regarding the extent to which patients with COPD with mild to moderate daytime hypoxemia not qualifying for longterm oxygen therapy (LTOT) experience transient nocturnal desaturation.
Fletcher 13 showed that 27% of 135 patients with COPD with awake PaO 2 exceeding 60 mm Hg had SIH.Although patients with REM-associated SIH had a lower awake PaO 2 and higher awake PaCO 2 , these parameters were not predictive in identifying patients with SIH.Subsequently, several small studies of patients with COPD reported the prevalence of significant nocturnal desaturation to be approximately 50% in patients who had some degree of daytime hypoxemia. 14,15Similarly, after screening more than 800 patients with COPD, Lewis et al 16 found nocturnal desaturation in 29 of 59 (49%) patients with a daytime SpO2<95%.In another study, up to 25% of patients with COPD exhibit SIH, despite having a daytime PaO 2 above 60 mm Hg. 17 There were two large studies of patients with COPD to assess the prevalence of nocturnal desaturation in 2011.Lacasse et al 18 found that a significant proportion (38%) of patients with moderate-to-severe COPD who did not qualify for home oxygen therapy based on their daytime PaO 2 had nocturnal oxygen desaturation without evidence of sleep apnea.This study found that nocturnal desaturation without sleep apnea could not be predicted by any patient characteristic or physiological measure and Home oximetry was an effective practical method for screening this population.Another study included a wide range of unselected individuals with COPD and reported that 20 of 103(19.4%)patients had significant nocturnal desaturation. 19Results from this study suggested that monitoring oxygen saturation changes during a 6 min walk test was useful in helping to identify COPD patients who would experience significant nocturnal desaturation.
Koo 20 found a mean decrease in PaO 2 of 13.5 mm Hg and a mean increase of PaCO 2 of 8.3 mm Hg during REM sleep.In a study of 16 COPD patients, 3 the mean SaO 2 was 90 ± 6% and the lowest SaO 2 during the night was 83 ± 8%.The percentage total sleep time (TST) with a SaO 2 less than 90% was 37 ± 45%.In another study, PaCO 2 increases 3 to 10 mm Hg, and PaO 2 decreases 2 to 8 mm Hg. 12 Compared to their nonhypoxemic brethren, hypoxemic COPD patients have greater degrees of pulmonary hypertension and cor pulmonale, require more frequent hospitalizations, and sustain higher mortality rates.
Pulmonary hypertension has been associated with SIH 21 The increase in pulmonary artery pressure was associated with the decrease in PaO 2 and less so with the increase in PaCO 2 .Profound hypoxemia and hypercapnia can occur in REM sleep and contribute to the development of cor pulmonale. 22Pulmonary vascular remodelling in COPD is the main cause of increase in pulmonary artery pressure and is thought to result from the combined effects of hypoxia, inflammation and loss of capillaries in severe COPD. 23rgi 24 found that SIH in COPD patients may represent an independent risk factor for the development of chronic respiratory failure in COPD patients with daytime PaO 2 > 60 mm Hg.Survival may also be affected by the presence of SIH in COPD.In a retrospective study of 169 patients with COPD, Fletcher 25 noted significantly decreased survival among patients with SIH compared with those without.Multiple regression analysis showed that quality of sleep was the best predictor of quality of life in subjects with COPD.Increased efforts to diagnose and treat sleep problems, including measures to improve factors that adversely affect sleep should receive great attention in the daily management of these patients, 26 but isolated nocturnal desaturation was not associated with impairment of sleep quality or daytime function. 16stematic inflammation is positively activated by SIH.Although nocturnal hypoxemia does not reduce exercise capacity or hand-grip strength in patients with mild/moderate COPD, its effect on maximal exercise diastolic blood pressure seems to depend on the degree of hypoxemia.In addition, there is a positive relationship between maximal inspiratory pressure and mean peripheral oxygen saturation during sleep, as well as evidence of pronounced inflammatory activation in patients with nocturnal hypoxemia. 27tients with COPD demonstrated significantly worse results in terms of accident frequency in the simulated driving situation because of SIH 28 and had a high prevalence of restless legs syndrome related with SIH. 29

Treatment of isolated SIH in COPD: Is it necessary?
The necessity of treatment of isolated SIH in COPD has been debated for lots of years. 30The specific effect of worsening of hypoxaemia during sleep is difficult to assess.Whatever the specific role of sleep-related oxygen desaturation in severely hypoxaemic COPD patients, such individuals are usually treated with LTOT according to usual criteria. 31,32Fletcher 33 found no improvement in mortality but did demonstrate a hemodynamic benefit when patients with normal daytime oxygenation but nighttime hypoxemia received oxygen during sleep.Oxygen therapy during sleep was found neither an improvement in survival despite a reduction in pulmonary artery pressures nor a delay in the time to prescription of continuous oxygen therapy. 25,33And some other randomized controlled trials of nocturnal oxygen treatment failed to demonstrate any improvement in pulmonary hemodynamic. 34When LTOT is started, the oxygen flow is individually adjusted to increase PaO 2 to > 60 mm Hg. 32,35 Such a flow may be insufficient during sleep.American Thoracic Society guidelines 32,36 for diagnosis and treatment of COPD recommended increasing oxygen flow by 1 L/min during sleep in patients undergoing LTOT to prevent nocturnal oxygen desaturation.However, those recommendations were not supported by any formal study demonstrating frequency of nocturnal desaturation in COPD patients breathing oxygen. 7,36,37Because most patients did not exhibit overnight desaturation despite not increasing their LTOT prescription overnight, so, these results challenge the recommendation of routinely increasing overnight oxygen flow in patients receiving LTOT. 38,39If sleep-related hypoxaemia has no effect on the outcome of the disease, prescription of oxygen during sleep would be a waste of medical resources.
Nocturnal non-invasive positive pressure ventilation (NNIPPV) is recommended to treat severe, stable COPD remains controversial, although a subgroup of patients with hypercapnea and sleep-disordered breathing (SDB) seems most likely to respond favorably. 40In a study, rehabilitation with nocturnal NIPPV resulted in the 6-minute walk test and in the longest non-stop walk distance in improvements.Further significant improvements were found for FEV 1 , lung hyperinflation, and blood gases in the NNIPPV treated, but not in the control subjects in advanced stage COPD. 41But a metaanalysis 42 of clinical trials did not support the treatment of NNIPPV for isolated SIH in COPD.Another study 43 did not furnish compelling evidence to change this point of view.McEvoy thought, compared with LTOT alone, NNIPPV resulted in a small improvement in survival.FEV 1 and PaCO 2 measured at 6 and 12 months were not different between groups.Patients assigned to NNIPPV + LTOT had reduced general and mental health and vigor. 44

Drugs for SIH in COPD
Pharmacological therapies which ameliorate some of the factors contributing to hypoxemia during sleep described above might be an alternative approach.Previous studies support an improvement in lung function as an im portant mechanism of improvements in SaO 2 during sleep.The Bronchodilators is the most commonly used drugs in patients with COPD.Oral theophylline therapy reduces the degree of air trapping in the lungs with consequent improvements in sleep SaO 2 . 45Postma et al 46 found that the nocturnal fall in SaO 2 occurring in COPD patients was abolished by the B-agonist terbutaline in a slowrelease oral form, which was also associated withan improvement in FEV1.However B-Agonists in this form are now rarely used.Long-acting B-agonists (LABA) are a recommended part of care in patients with moderate/ severe COPD.The recent study 47 assessed the effect of inhaled salmeterol on nocturnal sleeping arterial oxygen saturation and sleep quality and the findings indicated that addition of the inhaled LABA salmeterol improves SaO 2 during sleep in patients with advanced COPD.Based on the pulmonary function testing results the authors proposed a reduction in hyperinflation as one likely underlying mechanism in this improvement.However, another double blind randomized study evaluated short term effect of a single evening dose of formoterol or tiotropium on the isolated nocturnal hypoxemia in a group of patients with moderate to severe stable COPD and diurnal PaO 2 > 60mmHg and reported that formoterol did not seem to influence the nocturnal hypoxemia in stable COPD patients probably for the worsening V/Q ratio but tiotropium seemed to improved the nocturnal desaturations probably due to the reduction in the nocturnal bronchial cholinergic tone. 48ere are ongoing controversies concerning the safety of long-acting B-agonists, and therefore the inhaled longacting anticholinergics may represent the best choice of therapy for SIH in COPD and the multicenter study assessed the effect of the long-acting anticholinergic agent tiotropium and reported a significant improvement in SaO 2 during sleep, which was accompanied by an improvement in spirometry. 49re recently, as part of the National Emphysema Treatment Trial, lung volume reduction surgery has been shown to improve both sleep quality and nocturnal oxygenation in COPD.Although indications for performing an overnight polysomnogram in patients with COPD have been debated, recommendations have been presented.Future studies investigating disease mechanism and response to therapy in patients with sleep abnormalities and severe COPD are warranted. 17nce combined effects of inflammation, endothelial cell dysfunction, and angiogenesis appear to contribute to the development of pulmonary hypertension associated with COPD.Systemic vasodilators have not been found to be effective therapy.Selective pulmonary vasodilators including inhaled nitric oxide and phosphodiesterase inhibitors are promising treatments for patients with COPD associated pulmonary hypertension but further evaluation of these medications is needed prior to their routine use. 50nventional hypnotics worsen nocturnal hypoxemia and, in severe cases, can lead to respiratory failure.As a recent medicine, melatonin can improve sleep in COPD.Further long-term studies involving larger number of patients are needed before melatonin can be safely recommended for the management of sleep disturbances in these patients. 51r systematic inflammtion, methylprednisolone in combination with conventional medical therapy can not only improve lung function values but also mean nocturnal oxyhemoglobin saturation and sleep duration in clinically stabilized COPD patients who experience nocturnal oxyhemoglobin desaturation. 52e prevalence of SIH in patients with COPD is high.Determination of SIH may be important because it may impact on sleep quality, extrapulmonary comorbidities and health status of life in COPD.Perhaps most clinically relevant, nocturnal oxygen desaturation is a marker of increased mortality in COPD.However the relevance of evaluating nocturnal hypoxemia in patients with COPD is still under debate.A large multi-center research should be necessary to evaluate the adverse consequence of SIH and the benefit of correcting isolated SIH on longterm mortality rates in patient's with COPD.
Alveolar hypoventilation appears to play a major role, especially during REM sleep.This was demonstrated by Becker 9 in a study of nine patients with underlying COPD.Compared with wakefulness, minute ventilation decreased 16% during non-REM sleep and 32% during REM sleep, predominantly because of a decrease in tidal volume, measured with a pneumotachograph.