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Determinants of daytime hypercapnia in obstructive sleep apnea: is obesity the only one to blame?

I n contrast with COPD patients, patients with obstructive sleep apnea (OSA) have a priori normal respiratory mechanics and normal gas exchange during wakefulness. Increased upper airway resistance on sleep onset in OSA patients leads to intermittent or sustained alveolar hypoventilation during the night, but this process usually reverses within a short time after the patients wake up. However, about 30 to 40% of patients with OSA will continue to exhibit elevated Pco2 levels throughout the waking period, despite the absence of severe lung disease. In other words, OSA patients are at high risk for hypoventilation syndrome. Therefore, our primary gut feeling would be to attribute the daytime alveolar hypoventilation in patients with OSA to obesity, since it has been clearly implicated in the pathophysiology of OSA patients.1–4 Furthermore, we have now all become familiar with obesity hypoventilation syndrome (OHS), a complex condition that associates morbid obesity with severe daytime gas exchange abnormalities,5 such that we may have intuitively associated the daytime hypercapnia of OSA patients with obesity. In this issue of CHEST, we are reminded that, as is usual in medicine, things are not so simple. Indeed, Akashiba and colleagues (see page 415) report on their analysis of potential correlates of daytime hypercapnia in 143 male patients with OSA. Using a stepwise logistic regression approach, these investigators found that 43% of the variance in daytime Paco2 levels could be attributed to the mean oxyhemoglobin saturation during sleep and to the degree of vital capacity dysfunction, while the body mass index and the apnea index did not emerge from this analysis as exerting any additional effect on the predictive value of the model. Taken together, these findings would suggest that respiratory mechanics and nighttime hypoxemia may interact during sleep and during wakefulness in patients with OSA. How do we reconcile these findings with those from patients with OHS? A unifying concept for the pathogenesis of OHS has been formulated in a recent editorial in CHEST by Teichtahl.6 Respiratory muscle fatigue and diminished ventilatory response to a respiratory load,7 adverse respiratory mechanics and decreased leptin levels or leptin receptor density, which may attenuate hypercapnic ventilatory responsiveness,8–10 may all interact to promote the development of OHS. However, while the possibility of respiratory muscle fatigue in patients with OSA has not been explored systematically,11 leptin levels are not low but, rather, have been found to be elevated in these patients!12 Indeed, the mean ( SD) leptin levels were 13.7 1.3 ng/mL in 32 male patients with OSA whose conditions were newly diagnosed and had never been treated, and 9.2 1.2 ng/mL in 32 similarly obese, closely matched subjects (p 0.02).12 Thus, if leptin is indeed a modulator of central chemosensitivity, then OSA patients would be expected to display enhanced rather than attenuated CO2 ventilatory responses. An alternative explanation to the daytime hypercapnia of OSA patients could involve the characteristics of the events occurring during sleep. This explanation, which is based on the observation that eucapnic and hypercapnic OSA patients do not exhibit major differences in the number and duration of apneic episodes that they experience during the night,13 proposes that the ventilatory output during sleep will play a major deterministic role in the daytime ventilation characteristics of OSA patients.14 Rapoport and colleagues14 identified the following two major components affecting daytime gas exchange in OSA: (1) the occurrence of sustained hypoventilation independent of apnea and therefore not reversed by continuous positive airway pressure therapy, which would primarily reflect a low level of ventilatory drive in the awake state; and (2) a critical interdependency between the overall ventilation during the time spent awake and asleep, and the degree of CO2 loading induced by the apneic episodes that is not compensated for during the postapnea period.14 This second component was reversible with treatment of the apnea, such that conceptually, the balance between the kinetics of CO2 accumulation and elimination during the apnea and interapnea periods would impose the resultant Paco2 level during the daytime. Thus, we could interpret the findings of Akashiba and colleagues as being indicative of close interactions between a ventilatory debt incurred during OSA-disturbed sleep (which can be modified by effective therapy) and intrinsic individual factors associated with respiratory drive and gas exchange. In this context, breath-by-breath measurements of CO2 and O2 levels during sleep and wakefulness may provide important insights into the potential imbalances in CO2 homeostasis that are generated during sleep in patients with eucapnia and hypercapnia during the