Persistent sleepiness in CPAP treated obstructive sleep apnea patients: Evaluation and treatment

Summary

Nasal continuous positive airway pressure (CPAP) is an effective treatment for most patients with obstructive sleep apnea syndrome (OSAS), improving sleepiness, cognitive function and mood. A number of patients, however, complain about persistent sleepiness after CPAP. In these cases another clinical history should be carried out to confirm the diagnosis of OSAS, to check CPAP compliance and to exclude associated conditions such as poor sleep hygiene, depression, narcolepsy or idiopathic hypersomnia. If necessary, a full polysomnography (PSG) followed by a multiple sleep latency test or even a full PSG with CPAP titration should be performed. Experimental data in animals suggest that long-term intermittent hypoxia related to the apneic events could deteriorate the brain structures that regulate alertness. This impairment, if present in humans, could be another reason for residual sleepiness after CPAP. Modafinil has been shown to reduce subjective sleepiness after CPAP in OSAS patients. Further studies are warranted to clarify the way in which CPAP modifies sleepiness.

Introduction

Nasal continuous positive airway pressure (CPAP) is an effective treatment for many patients with obstructive sleep apnea syndrome (OSAS). It reduces sleep fragmentation, oxyhemoglobin desaturations and excessive daytime sleepiness (EDS) and improves cognitive function and psychological well being.1, 2 This improvement occurs soon after initiating CPAP in most patients, and is maintained over time. There are some patients, however, who despite a significant reduction in sleep disordered breathing with CPAP therapy show little improvement in their daytime sleepiness. This problem is not uncommon in everyday clinical practice although its prevalence is not well documented. Only one study, to our knowledge, reported that “tiredness, fatigue and/or sleepiness” persisted in 5% of 4218 OSAS patients after appropriate treatment—with CPAP in most cases but also with surgery or intraoral devices in a lower percentage.³ A number of clinical trials with stimulating drugs in these patients have been performed in recent years,4, 5, 6 highlighting the importance of this problem.

When treating a patient with persistent sleepiness after CPAP, a review of the clinical history to confirm the diagnosis of OSAS and a verification of CPAP pressure and compliance are mandatory. Furthermore, associated problems such as bad sleep hygiene, treatment with sedating drugs or an undiagnosed coexisting sleep disorder such as narcolepsy must be excluded. Nevertheless, after excluding all these factors, there is a group of CPAP treated OSAS patients who continue to complain of sleepiness. Why? A number of concerns need to be addressed before answering this question.

Since obstructive sleep apnea usually fragments sleep and sleep fragmentation causes sleepiness in healthy subjects, it is believed that obstructive sleep apnea is the sole cause of sleepiness. Restoring sleep continuity, it is assumed, reduces sleepiness in all patients. Sleepiness, however, may not be an inevitable consequence of obstructive sleep apnea. In fact, obstructive sleep apnea is a risk factor for sleepiness rather than its direct cause.⁷ For example, the prevalence of an apnea/hypopnea index (AHI) >5 is 17–24% in the male population but the prevalence of AHI >5 and sleepiness is only 3.1–4.1%.⁷ The relationship between the AHI and sleepiness measured either with the Multiple Sleep Latency Test (MSLT), the Maintenance of Wakefulness Test (MWT) or the Epworth Sleepiness Scale is not very close.8, 9 The range of daytime alertness is fairly wide at all levels of sleep apnea,⁸ suggesting that other mechanisms play a role in inducing sleepiness in OSAS patients. For example, obesity¹⁰ and snoring,¹¹ two common features in OSA patients, are both associated with EDS regardless of the respiratory disturbance index. Although snoring disappears with CPAP, obesity does not usually change with this treatment, which could at least in part account for this residual sleepiness. Residual sleepiness after CPAP does not seem to result from persisting sleep fragmentation, periodic leg movements of sleep (PLMS)¹² or from hypoxemia prior to CPAP treatment (at least the hypoxemia measured during the baseline sleep study).¹³ Finally, it should be pointed out that sleepiness is a common symptom in the general population, and probably results from sleep deprivation. This type of sleepiness will not improve with CPAP.

There is reliable evidence suggesting that CPAP reduces sleepiness more often than placebo in OSAS,¹⁴ with a mean reduction in the Epworth sleepiness scale score of 4.75 points and a mean increase in the MSLT/MWT of 0.93 min. This is consistent with the clinical experience of many patients reporting significant improvement in their sleepiness level with CPAP. However, the few studies that have measured sleepiness after CPAP and compared it with normal controls (Table 1) have shown that sleepiness in treated patients remains higher than in controls, even in patients who do not complain about it.

This is in line with other studies showing that MSLT/MWT values after CPAP may be abnormal,18, 19, 20, 21 a result that is less evident using Epworth sleepiness scale.1, 2 Although more information is needed, this suggests that factors other than apneas play a role in sleepiness both before and after CPAP. If objectively measured sleepiness persists, why do some patients complain about it more than others? To answer this question we need studies that compare CPAP treated patients who complain of sleepiness with those who do not.

Most of the measures used in everyday practice to evaluate the response to CPAP therapy are not objective. We simply ask the patient how he/she feels compared with baseline, particularly regarding nocturnal sleep and daytime sleepiness. This procedure differs from those in other medical disorders (diabetes, renal failure, etc.) where laboratory tests are routinely used to monitor treatment response, despite resembling those used in some neurological disorders (headache, pain, numbness, weakness…) or most psychiatric diseases. Since objective measures of sleepiness are not routinely used to follow up the response to CPAP, the variability of these tests in treated patients is unknown.

Sleepiness is not a clear-cut concept and may reflect different states.¹² Like hunger or thirst it is a basic, universal experience that is difficult to define and measure. Despite the existence of a large number of techniques that measure sleepiness, there is no one method that is definitive. Both objective and subjective methods have their limitations. A consistent finding in studies measuring the effects of CPAP on neuropsychological function is the presence of mood improvement¹ but it is not known whether improvements in mood and sleepiness are parallel in all patients. Depressed patients may describe the lack of energy or drive that is typical of depression as “sleepiness”²² despite normal MSLT results.

Guilleminault et al.³ reported that the MSLT is normal and the Epworth Sleepiness Scale minimally abnormal in most patients with “sleepiness, tiredness or fatigue” after CPAP and Bardwell et al.²³ found that depressive symptoms are dramatically associated with worse fatigue in OSA patients, independently of the AHI. It is therefore possible that the complaint of persistent “sleepiness” after CPAP is in part a description of lack of improvement in mood.

Since in CPAP-reated OSAS patients the MSLT and MWT detect less improvement in sleepiness than the Epworth sleepiness scale, it could also be postulated that part of the decrease in sleepiness is due to an improvement in the well being and depression/anxiety status of the patient that is better detected by the Epworth sleepiness scale or to a selective placebo-related additional effect with the subjective measures. A placebo effect of CPAP in the treatment of sleepiness has been consistently reported.¹ It is possible that in these cases, once the initial “honeymoon” period is over, patients may realize that sleepiness deteriorates when in fact what has occurred is a return to the baseline mood level. An alternative perspective is that the level of alertness/performance achieved during the first weeks of CPAP is higher than any other ever experienced by the patient. After several weeks of treatment this rebound “hyperalertness” would disappear making the patient complain of a loss of CPAP efficacy. In theory, this possibility could be assessed clinically by a brief period of CPAP discontinuance followed by reinstitution of CPAP to determine if improved alertness returns.

The severity of the residual sleepiness in CPAP treated OSAS patients who have no other associated conditions is probably lower than that occurring in narcolepsy or untreated OSAS, particularly when sleepiness is measured with objective tests. For example, in most patients with “sleepiness, tiredness or fatigue” after CPAP studied by Guilleminault et al.³ the Epworth sleepiness scale was only minimally abnormal and the MSLT was normal and in the three modafinil studies of residual sleepiness after CPAP,4, 5, 6 the mean baseline Epworth sleepiness scale scores were around 14–16, whereas the MSLT (around 7 min) or the MWT (14–16 min) were clearly less abnormal than in patients with untreated OSAS (see Table 1) or narcolepsy (MSLT: 3.3 min; MWT: 5.1 min).²⁴