New modalities are helping present better treatment options.
Chronic hypoxia has long been recognized as one of the most important factors contributing to the development of pulmonary hypertension and right ventricular failure.1,2 Many patients with chronic obstructive pulmonary disease (COPD) are chronically hypoxic and, often, hypercapnic. Obstructive sleep apnea (OSA), which produces intermittent hypoxia, may also be associated with pulmonary hypertension and right ventricular failure, and recent studies3-5 have shown that this can occur even in the absence of daytime hypoxia.
OSA and COPD are both common conditions. OSA, as documented on polysomnographic overnight sleep studies and associated with symptoms of daytime sleepiness, occurs in 2 percent of women and 4 percent of men aged 35 to 60 years.6 The latest data from the United Kingdom indicate that 4 percent of women and 9 percent of men over the age of 45 years have COPD.7
The term overlap syndrome was coined in 1985 to describe patients who have both COPD and OSA.8 It has since been recognized that the coexistence of OSA and COPD is associated with a definite increase in morbidity and a probable reduction in survival. Making an accurate diagnosis of this condition has become even more important as new modalities of treatment have been developed.
OSA is a condition characterized by repetitive episodes of upper-airway obstruction in sleep, leading both to sleep fragmentation and to periodic nocturnal hypoxemia (and, often, to hypercapnia). The long-term sequelae of OSA include increased cardiovascular morbidity and mortality,9,10 impaired neuropsychological function,11,12 and excessive daytime somnolence.13 Conflicting results have been reported regarding the control of breathing in patients with OSA. In general, however, normocapnic OSA patients demonstrate normal ventilatory responses to carbon dioxide stimulation,14,15 whereas those with chronic hypercapnia have depressed ventilatory responses to carbon dioxide.16,17
Data from a number of studies3-5 indicate that 10 percent to 20 percent of patients with OSA suffer from sustained daytime pulmonary hypertension. In addition, many patients with OSA, even without pulmonary hypertension, have right ventricular dysfunction. A few studies3,18 of patients with combined OSA and COPD have shown the prevalence of pulmonary hypertension to be as high as 70 percent to 80 percent.
Patients with severe COPD may be hypoxic/hypercapnic during the daytime, and there is often a significant worsening of their gas exchange during sleep. These patients characteristically hypoventilate during sleep, particularly in rapid eye movement (REM) sleep; this leads to nocturnal desaturations and carbon dioxide retention.19 The mechanisms involved include altered brain-stem function, diminished ventilatory responses, and muscular hypotonia. In a number of patients, however, the decrease in minute ventilation also occurs because of the added increase in upper-airway resistance. As a consequence, severe hypoxia/hypercapnia follows, frequently leading to the development of overt respiratory failure, pulmonary hypertension, and (eventually) right ventricular failure.
REM sleep hypoventilation may also result in cardiac arrhythmias,20 pulmonary hypertension,21 impaired sleep quality,22 and nocturnal death.23
Patients with the overlap syndrome frequently show profound and prolonged hypoxemia during sleep. Usually the baseline oxygen saturation level does not recover between episodes of repetitive apnea. This may be a very important factor in contributing to the increased prevalence of cor pulmonale24 and pulmonary hypertension25 in these patients. In a study by Radwan et al,26 ventilatory responses during carbon dioxide rebreathing were compared for patients with OSA alone, patients with the overlap syndrome, and controls. There were no differences in ventilatory response between patients with OSA and controls, but patients with the overlap syndrome had significantly depressed responses. The results of this study suggest that the presence of COPD in patients with OSA explains this depressed response and may, at least partially, explain the increased prevalence of daytime respiratory failure and pulmonary hypertension in these patients.
There are many technical difficulties involved in measuring airflow during sleep. Thermal devices are used in some sleep laboratories, but they measure changes in temperature related to expiration, not airflow. Similarly, the recording of thoracic and abdominal effort is not a measure of airflow. Pneumotachography, although it gives an accurate airflow measurement, can contribute to nonrespiratory arousals because of the associated discomfort. The same is true of esophageal catheters that can assist in measuring upper-airway resistance. The use of nasal prongs attached to a pressure transducer is promising, but requires further study.
Because of these limitations in airflow measurement and, in particular, in the assessment of partial upper-airway obstruction, it is sometimes difficult to determine the precise pathophysiology of nocturnal desaturation in patients with COPD. Particularly in REM sleep, it may be difficult to differentiate between decreased ventilatory drive and partial upper-airway obstruction. This differentiation clearly has therapeutic implications. Long-term oxygen therapy improves survival in patients with COPD and chronic respiratory failure, but may not be optimal treatment for those patients with associated upper-airway obstruction, hypoventilation, or both.
Long-term Oxygen Therapy
In the early 1980s, landmark studies27,28 of supplemental oxygen therapy in patients with COPD and respiratory failure showed a clear survival advantage among those given oxygen, with the increased benefit attributable to increased oxygen use. Studies29-31 of oxygen therapy in OSA have revealed conflicting results. Most have shown no improvement in daytime function or apnea indices, despite improvement in nocturnal oxygen saturation. This is consistent with the view that oxygen therapy in OSA does not have a significant effect on the fundamental pathophysiological mechanism-namely, repetitive upper-airway obstruction. Studies on the potential benefits of oxygen therapy in the overlap syndrome are lacking. Clinical experience suggests that correction of nocturnal oxygen desaturation is incomplete and may be associated with worsening of nocturnal carbon dioxide retention.
Positive Airway Pressure
Limited data are available regarding this therapeutic option. One study32 has shown that patients with the overlap syndrome have improved daytime gas exchange and lowered pulmonary artery pressure when treated with continuous positive airway pressure (CPAP) therapy, but not when oxygen alone is used. In patients who remain hypoxemic despite CPAP, the addition of oxygen is probably beneficial. Improved oxygenation, without worsened hypercapnia, has been reported when oxygen is added to CPAP treatment for such patients.33
Noninvasive Positive-Pressure Ventilation
Successful treatment of OSA through the application of positive pressure to the upper airway via nasal mask has led to the application of nocturnal positive-pressure ventilation as therapy for chronic respiratory failure due to multiple causes, including COPD. To date, there have been four controlled studies34-37 assessing the efficacy of noninvasive ventilatory support during sleep in patients with advanced COPD. One study34 reported improvement in sleep quality, daytime gas exchange, and quality of life in association with such therapy, but the three other studies35-37 failed to show such an advantage. Clearly, more studies are required (with larger numbers of patients and longer durations of therapy) before valid conclusions can be made about the efficacy of noninvasive ventilation in patients with advanced COPD. In theory, at least, noninvasive ventilation could have a role in the treatment of patients with the overlap syndrome by eliminating both upper-airway obstruction and nocturnal hypoventilation. Patients with OSA were excluded from the four studies of noninvasive ventilation in COPD, and there are currently no published studies that assess the efficacy of noninvasive ventilation in patients with the overlap syndrome.
The overlap syndrome is not an uncommon clinical entity. It can lead to overt cardiorespiratory failure. It is probably associated with a worse prognosis than either OSA or COPD alone. Better methods are required for the accurate delineation of the mechanisms of nocturnal desaturation in overlap-syndrome patients. The role of noninvasive ventilation in patients with the overlap syndrome is yet to be determined. N
David J. Barnes, MBBS, FRACP, and Leon Laks, PhD, FRACP, are directors at the Camperdown Sleep Investigation Centre in Annandale, Australia.
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