key: cord-0783323-h39yfet7
authors: Mehra, Reena; Heinzer, Raphael; Castillo, Pablo
title: Current Management of Residual Excessive Daytime Sleepiness Due to Obstructive Sleep Apnea: Insights for Optimizing Patient Outcomes
date: 2021-10-18
journal: Neurol Ther
DOI: 10.1007/s40120-021-00289-6
sha: 8b21f0846075af803ddb0a8a3dc0f03d263f4c0e
doc_id: 783323
cord_uid: h39yfet7

Although excessive daytime sleepiness (EDS) attributable to obstructive sleep apnea (OSA) can be resolved by consistent usage of and effective treatment (often with the use of continuous positive airway pressure therapy), 12–58% of patients report residual EDS (REDS). While REDS is difficult to treat, a proportion of cases are possibly due to reversible issues, and wake-promoting medications can prove useful for the remaining cases. Given the challenges associated with effective management of REDS and its relationship to multiple comorbidities, multidisciplinary management of patients with REDS is often recommended. Here we aim to bridge the knowledge gap on the burden, risk factors, prevalence, and potential pathophysiologic mechanisms of REDS in patients with OSA after first-line treatment. The roles of primary care physicians and sleep specialists, as well as the importance of the use of objective assessment tools for the evaluation of REDS and the effective management of comorbidities, are discussed. An update of approved treatments and emerging candidate treatments is also presented.

Recurrent episodes of partial or complete pharyngeal collapse occurring during sleep are the characteristic features of obstructive sleep apnea (OSA) [1] , which is defined as an apnea-hypopnea index (AHI) of at least 5 events/h in association with symptoms such as unrefreshing sleep, daytime sleepiness, fatigue or insomnia, awakening with a gasping or choking sensation, loud snoring, or witnessed apneas [2, 3] . OSA is an established health concern that affects almost 1 billion people globally, with a prevalence that is increasing and can vary widely between countries [4] . The prevalence of moderate-to-severe OSA (defined as at least 15 events/h) is estimated to range from 25% to 36% in international-based assessments [4] . Patients with OSA have an increased risk of metabolic and cardiovascular (CV) comorbidities, as well as death [5, 6] .

Excessive daytime sleepiness (EDS), commonly defined using the standard validated instrument the Epworth Sleepiness Scale (ESS) utilizing a threshold score of greater than 10 [7] , is one of the most commonly reported symptoms of OSA, along with fatigue and neurocognitive dysfunction (e.g., compromise in focus and concentration, mood changes that mainly consist of increased irritability) [1, 6] . EDS is a public health hazard and remains underdiagnosed and undertreated, even in patients who already have a diagnosis of OSA [8, 9] . EDS in OSA has been shown to be associated with an increased risk of hospitalization and increased outpatient healthcare utilization [8] , as well as an increased risk of CV disease [10] . With negative effects not only on the individual but also on social interactions with family members and on a range of workplacerelated factors, EDS can compromise social interactions, diminish cognitive function, impair work productivity and school performance, and result in drowsy driving and decrements in quality of life (QoL) [11] [12] [13] [14] [15] . EDS has also been linked to depression, mood disturbances, behavioral challenges, and an increased risk of substance abuse in teenagers [16, 17] .

First-line treatment of EDS due to OSA is continuous positive airway pressure (CPAP) therapy [7] . CPAP has been demonstrated by meta-analysis to significantly reduce subjective daytime sleepiness (ESS 1.2-point reduction; 95% confidence interval [CI] 0.5-1.9; p = 0.001) and improve objective daytime wakefulness (Maintenance of Wakefulness Test [MWT] 2.1min improvement; 95% CI 0.5-3.7; p = 0.011) in patients with mild-to-moderate OSA [18] . However, despite optimal CPAP treatment, some patients have residual EDS (REDS). In a French study (n = 502), there was an estimated prevalence of REDS (indicated by an ESS score of at least 11) of 12% among patients with OSA despite adherence to CPAP treatment (i.e., a mean usage of 6.1 ± 1.3 h/night, which was above the defined threshold for adherence of mean CPAP usage of more than 3 h/night). After adjustment for potential confounding factors (i.e., depression, restless legs syndrome [RLS] , narcolepsy, medications influencing vigilance, suboptimal CPAP treatment), the estimated prevalence of REDS was 6.0% in patients with OSA who were adherent to CPAP treatment [19] . In other studies that used an ESS score of greater than 10 to indicate REDS, the prevalence of REDS ranged from 15.6% to 58.3% in patients with OSA who were adherent to CPAP treatment (i.e., more than 4 h/night); however, the prevalence of REDS decreased with increasing CPAP usage [1, [20] [21] [22] [23] .

Challenges remain regarding the evaluation and treatment of patients with REDS due to OSA despite effective adherence to CPAP therapy [7] . Even though primary care physicians are usually the first point of contact for patients with OSA, it is important to know when patients should be referred to a sleep specialist [9, 24, 25] . To help strengthen the knowledge base and advance the understanding of clinicians who typically treat patients with OSA, this narrative review summarizes the pathophysiologic mechanisms involved in EDS due to OSA and the current practices for managing these patients, including the appropriate use of assessment tools, current pharmacologic treatments, and emerging modalities. In addition, confounding factors, such as comorbidities, are discussed and management algorithms are suggested.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

The causes and mediators of the pathophysiology of EDS in OSA are multifactorial. Furthermore, the substantial inter-individual variability suggests that dynamic interactions between the mediators of EDS in OSA and the body's repair systems and local damaged tissues are involved. Apnea and hypopnea commonly end with arousal from sleep, which allows the upper airway to reopen and normal breathing to resume. Experimental mouse models that used an intermittent hypoxia intervention implicated cell injury and apoptosis in response to the activation of pathways of inflammation and oxidative stress, resulting in permanent neuronal damage in areas of the brain responsible for the regulation of wake and sleep [26, 27] . These areas of damage were associated with persistence of sleepiness even subsequent to return to the normoxic environment. The repeated arousal-induced sleep fragmentation that occurs in patients with OSA can alter the cyclic structure of sleep [26] . Sleep fragmentation and the hypoxia-reoxygenation cycle may induce inflammation and oxidative stress that may alter the health of wake-activating neurons [27, 28] . OSA potentially shifts the peak in melatonin secretion [29] and induces fragmented sleep, which may reduce the efficiency of the glymphatic transport system that is proposed to be important for waste removal in the Fig. 1 Gross anatomy showing presumed injured central nervous system regions involved in the generation of residual daytime sleepiness. Brainstem: Wake-promoting neurons: dorsal raphe nucleus, locus coeruleus (LC), and dopamine ventral periaqueductal gray wake neurons (vPAG). Brain: Hippocampus (entorhinal cortex), Amygdala (basolateral nucleus), left posterior parietal cortex, right superior frontal gyrus, and the white matter network (an anatomical substrate crucial for alertness) central nervous system during sleep (Fig. 1) [30] . Moreover, a study using diffusion tensor imaging revealed the presence of extensive alterations to white matter in CPAP-treated patients with REDS compared with patients without REDS; some of the alterations correlated with ESS scores [31] .

An autopsy study of individuals with OSA showed that those with severe OSA had greater hippocampal atrophy and demyelination than those with mild OSA [32] . Another study based on magnetic resonance imaging (MRI) and polysomnography data demonstrated that OSArelated hypoxemia reduced hippocampus volume (i.e., increased atrophy), which is consistent with previous studies [33] . Individuals who adhered to CPAP therapy in the autopsy study exhibited similar levels of demyelination but showed less atrophy of regions of the hippocampus (i.e., the dentate gyrus, the CA1, and deep layers of the entorhinal cortex) involved in memory pathways compared with individuals who were not known to adhere to CPAP therapy. Patients with OSA often have impaired episodic, spatial, and semantic memory; these impairments may be related to the demyelination and thinner cortical layers in the hippocampus, which is the location of the direct (semantic) and polysynaptic (episodic and spatial) memory pathways that begin in the entorhinal cortex [32] . The potential pathophysiologic mechanisms involved in the development of REDS in OSA are illustrated in Fig. 1 and discussed in more detail below.

Inhibition of hypothalamic orexin neuron activity caused by hypoxia and hypercapnia has been implicated as a causal mechanism of EDS in OSA [34, 35] . Rat studies have shown that acute hypoxia/hypercapnia rapidly inactivates orexin neurons, which may contribute to impaired function of orexin neurons in individuals with OSA [34] . Orexins are neuropeptides that play an important role in sleep-wake cycle regulation, helping to maintain both waking state and rapid eye movement (REM) sleep [36] [37] [38] [39] . Reduced orexin neuron activity and neurotransmission have been implicated in sleep disorders, including OSA. Also, downregulated plasma levels of orexin-A have been demonstrated in patients with OSA [34] .

There is also evidence that orexin contributes to respiratory regulation [36, 40, 41] . Orexin-A can activate expression of hypoxiainducible factor 1a (HIF-1a), a transcription factor with a role in ischemia and hypoxia [38] , as well as downstream targets of HIF-1a, such as vascular endothelial growth factor and erythropoietin [42] . Increases in orexin-A may also be involved in OSA-associated neurocognitive deficits, such as spatial memory and learning deficits. In a hypoxia model in cultured rat hippocampal neurons, orexin-A increased intermittent hypoxemia-induced hippocampal neuronal damage by overphosphorylation of extracellular signal-regulated kinase 1/2 through the orexin receptor-phospholipase C-b1 (PLCb1) pathway [43] . In addition, chronic exposure to hypoxia/hypercapnia has been shown to compromise neurotransmission from orexin neurons to parasympathetic cardiac vagal neurons [37, 44, 45] . Results from these rat studies suggest that exaggerated inhibitory neurotransmission from the lateral paragigantocellular nucleus to cardiac vagal neurons may lead to a sleep-associated high risk of tachycardia, arrhythmia, and sudden cardiac death in people with OSA [44].

Intermittent hypoxia exposure led to augmented oxidative stress and elevated inflammatory mediators in rodent animal models, which correlated with injury to wake-promoting neurons and supportive brain cells [26, 46] . For example, after mice were exposed to longterm intermittent hypoxia (LTIH) for 8 weeks, total daily sleep time and non-REM sleep were each lengthened by more than 2 h (an approximately 33% increase) upon return to normal oxygenation in LTIH-exposed mice compared with sham-treated mice. The wake-promoting regions of the basal forebrain and brainstem provided abnormal polysomnographic findings, and oxidative-injury measures were suggestive of oxidative stress and injury. After LTIH cessation, the LTIH-exposed mice also had significantly reduced mean sleep latency compared with sham-treated mice [26] . Another study demonstrated that even 6 months after an 8-week exposure to hypoxia-reoxygenation, irreversible injury was evident in the noradrenergic neurons in the locus coeruleus and the dopaminergic neurons in the periaqueductal gray area. Further, chronic sleep deprivation induced a significant 25% reduction (p \ 0.05) in orexinergic neurons compared with control mice [47] . Taken together, these data suggest that hypoxia-reoxygenation and chronic sleep deprivation can lead to the injury of multiple brain regions.

Inflammation induced by cycles of hypoxia-reoxygenation is considered one of the key underlying mechanisms of sleep-disordered breathing and EDS [7, 27] . Inflammatory cytokines (e.g., interleukin [IL]-6, IL-8, tumor necrosis factor-a) are often monitored as indicators of the inflammatory cascade. In patients with systolic heart failure, the inflammatory markers cortisol and IL-6 have been significantly associated with mean sleep latency (an objective measure of sleepiness) but not with ESS (a subjective measure of sleepiness) [48] . Since subjective and objective measures of sleepiness do not always correlate [49] , these data further support the possibility that underlying mechanisms may overlap but may also involve distinct mediators [48] . Other studies, including the prospective study by Chen et al., have suggested possible interactions between systemic inflammation and microstructural damage in the brain due to OSA-related hypoxia [50] .

Sleep fragmentation, a common consequence of OSA, may alter the efficiency of the glymphatic system. Rodent animal models were used to describe the glymphatic system, which is responsible for the efficient removal of waste from the brain during sleep. This paravascular cerebrospinal fluid transport system was twofold more efficient in removing waste (i.e., amyloid-b) during the slow-wave cycle in sleeping mice compared with awake mice [30, 51] . The possibility of an analogous transport system in human brains was explored using brain imaging with MRI in healthy participants during different sleep-wake phases. In this study, sleep-induced increases in cerebrospinal fluid volume in the whole human brain were observed, which supports the possibility of a paravascular glymphatic system in humans that may function to remove waste from the brain during sleep. Interestingly, this MRI study showed that several different brain regions, particularly the cerebellum, experienced diffusion changes at different phases of the sleep-wake cycle, suggesting a more complex rhythm in humans than in rodents [52] . Further research is needed to determine whether alterations in slow-wave sleep patterns in patients with OSA [28] cause changes in brain accelerated diffusion dynamics or the efficiency of waste removal.

A study showed an altered circadian rhythm of melatonin secretion in about 25% of patients with OSA (n = 18) and significantly lower peak melatonin levels in those with a preserved circadian rhythm of melatonin secretion compared with healthy participants [29] . Although evidence is limited, it may be interesting to investigate whether melatonin supplementation aids sleep efficiency and improves REDS in patients with OSA.

Dysbiosis has also been associated with OSA, with the richness and diversity of the microbiome of male individuals (n = 22; without a history of gastrointestinal illness or prior use of pharmaceuticals) being positively correlated with total sleep time (assessed by actigraphy over a 4-week period) [53] . Additionally, in a rat model of OSA, a high-fat diet led to hypertension within 7 days of OSA, with continued blood pressure increases at 14 days; the gut microbiota concurrently harbored fewer taxa that produce the short-chain fatty acid butyrate. Fecal transplants from hypertensive rats with OSA on a high-fat diet to normotensive rats with OSA on a normal diet led to induced hypertension within 7 days of OSA, with blood pressure increases continuing at 14 days [54]. Taken together, these data raise the possibility that specific genera in the nasal glands, salivary glands, and gut microbiomes of humans, coupled with lifestyle choices, may increase the risk for OSA, EDS, and hypertension.

Genetic factors may provide a higher risk for EDS in some populations. In the Multi-Ethnic Study of Atherosclerosis Sleep Cohort (n = 2230), EDS (according to an ESS score of greater than 10) was most prevalent in Blacks/ African Americans (18.8%) and Hispanic Americans (13.6%) and least prevalent in White Americans (11.4%) and Chinese Americans (11.1%). Furthermore, Blacks/African Americans had a significantly higher risk of EDS (odds ratio 1.89) and sleep apnea (odds ratio 1.78) compared with White Americans after adjustment for sex, age, and study site [55] . Moreover, an epigenome-wide association analysis of the Multi-Ethnic Study of Atherosclerosis Sleep Cohort revealed that one locus was associated with EDS in all ethnic groups (i.e., Blacks/African Americans, White Americans, and Hispanic Americans), and three additional loci were associated with EDS in Blacks/African Americans [56]. These results may help explain the higher risk for objective and subjective sleepiness detected in the African-American population despite adjusting for numerous confounding factors by multivariate analysis [57].

On the basis of clinical symptoms, a sleepy OSA phenotype has been characterized and is distinct from other subtypes of OSA, such as those with disturbed sleep symptoms and those with a relative lack of traditional OSA symptoms. Furthermore, the sleepy OSA phenotype has been associated with an increased risk of adverse CV outcomes, such as heart failure and coronary heart disease [10] . Given the increased CV risk observed in patients with EDS in OSA [10] and reported treatment benefits in CV outcomes (i.e., blood pressure), especially in sleepy (i.e., greater EDS and/or more severe OSA) versus non-sleepy OSA phenotypes [58, 59] , it is important that these patients receive adequate treatment. However, the Impact of Sleep Apnea Syndrome in the Evolution of Acute Coronary Syndrome: Effect of Intervention With CPAP (ISAACC) trial, a secondary prevention trial designed to evaluate the effect of OSA and the effectiveness of CPAP treatment on the clinical evolution and prognosis of patients with acute coronary syndrome, found that CPAP had no positive effect on the prevention of recurrent CV events in patients with OSA and acute coronary syndrome compared with usual care alone [60, 61]. However excessively sleepy patients were excluded from this trial.

Multiple perspectives encompassing a patient's comorbidities, health status, impact on daily living, and profession can help inform decisions regarding referral to a sleep specialist. Depending on the ESS score and clinical judgment, primary care physicians may consider referring their patients to a sleep specialist (Fig. 2 ). Since REDS, despite the apparent adherence to CPAP treatment, could be due to the presence of other treatable conditions, such comorbidities should be systematically ruled out. Some potentially treatable causes of REDS due to OSA (e.g., inadequate CPAP treatment, comorbidities, insufficient sleep due to other causes) are shown in Table 1 and discussed in more detail below [7] . Whenever possible, the priorities for the management of REDS due to OSA, before initiating pharmacologic intervention, are as follows: adjusting medications for comorbid conditions to those with less sedative effects, adjusting CPAP for optimal treatment effect, evaluating alternative PAP treatments such as oral appliance or hypoglossal nerve stimulation, ensuring sufficient sleep, identifying and treating depression, performing an assessment for other hypersomnia disorders such as narcolepsy, and establishing lifestyle changes are considered priorities for the treatment of EDS due to OSA before initiating pharmacologic intervention.

Patients with OSA often have comorbidities that may obscure the diagnosis of EDS. Moreover, patients with OSA and EDS have been shown to have more comorbid symptoms than those without EDS [62] . Known comorbid conditions of OSA include obesity, depression, anxiety, RLS, periodic leg movements, narcolepsy, and circadian rhythm disorders [7, [62] [63] [64] [65] [66] [67] . Screening of patients with REDS using the Beck Depression Inventory-II questionnaire, for Adapted with permission from Javaheri and Javaheri [7] CPAP continuous positive airway pressure, EDS excessive daytime sleepiness, OSA obstructive sleep apnea example, could help to exclude the presence of comorbid depression [68] . Also, screening for coexisting circadian rhythm disorders that may contribute to REDS is warranted, especially in commercial drivers and pilots [7] . Since sleep problems, such as OSA and EDS, have been associated with the current coronavirus disease 2019 (COVID-19) pandemic [69, 70] , post-COVID-19 fatigue should be ruled out as well. Also, treatment-emergent central sleep apnea should be considered as a cause of persistent sleepiness since it can develop during treatment of OSA with CPAP and is also associated with EDS [71] .

It is important to note that many of the aforementioned comorbid conditions may be treated using medications with somnolence-inducing adverse effects. Thus, a patient's medications should be examined to identify those that can induce drowsiness or sleepiness [7, 72] . Since some medications prescribed to treat depression (e.g., imipramine [an activating tricyclic antidepressant]) or anxiety (e.g., benzodiazepines) may augment the tendency toward sleepiness, medication adjustments may be needed to reduce this potential adverse effect [7, [72] [73] [74] . Among antidepressants, imipramine, doxepin, and amitriptyline are a few agents that are likely to cause sleepiness [73] . Sleepiness is also one of the associated side effects of dopaminergic agonists, which are often used to treat RLS and periodic limb movements in sleep [7, [75] [76] [77] . Other medications that can induce drowsiness include antihistamines (e.g., meclizine, hydroxyzine, diphenhydramine [Benadryl Ò ]); antihypertensive medications (e.g., beta-blockers), which often decrease the heart rate; muscle relaxants (e.g., carisoprodol, cyclobenzaprine), which often mediate effects on the brain; and opioid analgesics [7, 73, [78] [79] [80] . The combination of opioids with acetaminophen can disrupt sleep by causing increased awakenings, decreased slow-wave sleep, and suppressed REM sleep [73] .

As an initial step, it is important to ensure that current treatment is optimized. For example, the data of the CPAP device should be interrogated for its pattern of use, assessed for an excessive leak, and evaluated to ascertain the residual AHI of a patient. If it is obvious from these data that a patient's current treatment is not optimal, the physician should make appropriate adjustments. Adjustment of the CPAP apparatus for comfortable and effective nightly use may help improve airflow and treatment adherence. In some cases, lifestyle changes may expand the benefits of CPAP treatment sufficiently to improve a patient's QoL. For example, physical exercise combined with CPAP treatment has been demonstrated to improve QoL and subjective EDS [81] .

Alternative airway-directed therapies, such as positional therapy, mandibular advancement devices (MADs), or hypoglossal nerve stimulation are typically offered to patients who decline or do not tolerate CPAP and may also be useful in patients with REDS due to OSA despite CPAP adherence. The use of MADs has been associated with an improvement of symptoms in patients with mild-to-moderate OSA [49, 82] , and MADs may have a higher rate of adherence than CPAP [83] . As part of an individualized treatment plan, ablative surgery options, such as tonsillectomy, maxillomandibular osteotomy, or bariatric surgery for extreme obesity, may be suitable for selected patients with OSA and REDS [49] .

Various risk factors are reportedly associated with REDS after CPAP. A French study in 1047 patients with OSA treated with CPAP for more than 3 h/day showed that high baseline degree of OSA (defined by the AHI) and depression were independent predictors of REDS. Patients with REDS also were more likely to be female and had generally worse health [1] . Other reported risk factors of REDS include a high pretreatment ESS score, age less than 55 years, and a history of diabetes and heart disease [19, 21, 23] . REDS has also been associated with upper airway resistance syndrome (UARS) [84] . UARS affects proportionately more women than men and is characterized by a narrowing of the posterior airway space behind the base of the tongue [84, 85] . When left untreated, UARS can negatively affect QoL and has CV and metabolic consequences; thus, it is important to rule out 

There are many subjective (Table 2 ) and objective (Table 3 ) clinical tools available for the assessment of REDS. Subjective measures are an efficient and cost-effective way of estimating EDS. Completion of a sleep diary by a patient for 2 weeks could provide useful information. Also, the ESS is a commonly used subjective questionnaire that captures a patient's self-reported likelihood of falling asleep on a scale of 0 (never) to 3 (high chance of dozing) under eight different everyday scenarios [86] . Validation in a large clinical sample demonstrated that the ESS provides an accurate measure of daytime sleepiness that is interpreted similarly across all patients [87] , and item-response theory analyses confirmed the reliability of the ESS as a measure of the propensity to sleepiness [88] . ESS scores range from 0 to 24, with EDS often defined as a score of greater than 10, and EDS severity is categorized according to ESS scores of 11 to less than 15 (mild), 15 to less than 18 (moderate), or 18 to 24 (severe) [89] . To minimize completion times, shortened versions of some self-reported questionnaires may be used where available.

Time to completion is about 5 min for ESS, so it can easily be completed during an office visit [90] . Digital integration in subjective reporting instruments also assists in enhancing the efficiency of data collection and allows for the ability to follow trends in response to treatment interventions. However, subjective measures of sleepiness as a sole test may be unreliable in some clinical situations [13] . For example, known adaptation of a patient's perception toward chronic sleep deprivation may cause discrepancies between subjective sleep quality and objective assessments of sleep (i.e., either a poorer perception of sleep vs. objective measurement or perceived good sleep when there is objective sleep disruption) [91] . The ability to disregard symptoms of sleepiness helps to explain why EDS remains underdiagnosed and underreported, as well as the poor correlation observed between ESS scores and AHI or objective measurements (such as the Multiple Sleep Latency Test [MSLT]) [49]. Indeed, a dissociation between self-reported EDS and objective sleepiness has been noted in patients with OSA and heart failure, with some patients having a mean sleep latency of 5 min or less despite normal ESS scores and biomarkers The extent of REDS and its impact on a patient with OSA may be more accurately measured with input on the ESS from a partner or with the addition of focused questions from the physician [13, 49] . Additionally, in the context of the clinical history of a patient, whenever possible, results of subjective measures should be confirmed with objective measures (Table 3) , especially when a patient has a high-risk occupation (e.g., commercial driver, pilot) [13, 49, 92] . Use of actigraphy may help to exclude other sleep disorders (e.g., compartmental sleep deprivation, ''insufficient sleep syndrome'') as potential reasons for REDS. Many of these assessments are only available at specialist sleep centers; thus, referral to a sleep specialist may be required. It would also make sense to perform an objective assessment of sleepiness (e.g., MSLT, MWT) before considering additional medications for patients with REDS, although these tests are currently not a requirement in all countries [92] . Laboratorybased objective measures of sleepiness and [92, 93] . The MSLT is indicated in patients with suspected narcolepsy to confirm the diagnosis and may be used to help differentiate idiopathic hypersomnia from narcolepsy. The MWT may be used to assess an individual's ability to remain awake when his or her inability to remain awake constitutes a public or personal safety issue (i.e., in individuals with OSA, narcolepsy, or other sleep disorders who are employed in occupations involving public transportation or safety that may require assessment of their ability to remain awake). While the MWT may be used to assess response to treatment in patients with excessive sleepiness, the MSLT is not routinely used in this indication [92] .

In addition to airway-focused therapy, wakepromoting medications have a core adjunctive role in improving REDS in patients with OSA. Wake-promoting medications have been shown to improve REDS (Table 4) ; however, their prescription in many countries is limited to specialist physicians only. In addition, because of adverse CV effects seen with some agents, a pretreatment electrocardiogram and/or input from a cardiologist is required in some countries. Nevertheless, there are no guidelines regarding CV recommendations prior to prescription of wake-promoting medications. Table 4 outlines the efficacy, safety, and CV tolerability of currently available medications for REDS. While modafinil/armodafinil is approved in the USA [94, 95] and was initially approved in Europe, the European Medicines Agency advised physicians in 2010 to no longer prescribe modafinil for the treatment of excessive sleepiness associated with OSA, idiopathic hypersomnia, and chronic shift work sleep disorder because of concerns about risks of neuropsychiatric disorders and particular CV risks in patients with cardiac arrhythmias and uncontrolled hypertension [96] . Lower CV risk has been observed with solriamfetol and particularly with pitolisant (H 3 receptor antagonist/inverse agonist) than has been observed with modafinil (Table 4 ) [97] [98] [99] [100] . Solriamfetol is approved for the treatment of EDS in OSA in the USA and in Europe [98, [101] [102] [103] . In addition, pitolisant has been studied for EDS in OSA in the USA and in Europe [97, 104, 105] ; it is approved in the USA for the treatment of EDS in narcolepsy [106] and in Europe for the treatment of EDS in OSA [107, 108] . In light of observed adverse CV effects with solriamfetol, periodic monitoring of vital signs is suggested (e.g., every 6 months initially or yearly) [101] . Also, concurrent use of solriamfetol with a monoamine oxidase inhibitor is contraindicated because of the increased risk of hypertensive reactions [101] , and concurrent use of pitolisant with drugs that may prolong QT interval should be avoided [106] .

Emerging Therapies for EDS Due to OSA TAK-925 is a hypocretin/orexin-2 receptor-selective agonist that is currently under clinical development for EDS [109] . A phase 1 randomized, double-blind, placebo-controlled, crossover clinical trial investigating the safety and pharmacokinetics of TAK-925 in 25 patients with EDS due to OSA despite adequate use of CPAP was completed in April 2020. TAK-925 was administered as an infusion, and drug concentrations in the blood were determined at multiple time points during infusion (up to 9 h) and afterwards (up to 15 h). The primary outcome was the safety profile of TAK-925 (treatment-emergent adverse events, abnormal clinical safety laboratory tests, vital signs, and 12-lead electrocardiogram parameters), and secondary outcomes included pharmacokinetics and pharmacodynamics [110] . Results have not yet been published [110] but are awaited with interest. TAK-925 is also being investigated for the treatment of EDS in patients with narcolepsy. Other compounds are being investigated for treatment of EDS in narcolepsy, including FT218, JZP-258, AXS-12, THN102, CONCLUSIONS REDS, despite adherence to CPAP, is challenging to evaluate and treat, and is associated with considerable health burden. Multifactorial pathophysiologic mechanisms, including chronic hypoxia-reoxygenation-induced injury to orexinergic neurons, genetic factors, oxidative stress, dysbiosis, inflammatory issues, altered melatonin circadian rhythms, sleep fragmentation, and possible disturbances of the glymphatic system, may not be completely reversed after OSA is treated. Subjective measures of sleepiness, such as the ESS, may have limited effectiveness in identifying patients with REDS; thus, referral of patients to a sleep specialist for objective testing is necessary to correctly identify those requiring further treatment. Initial management of REDS due to OSA includes evaluation of comorbidities, replacing sleep-promoting medications, and optimizing CPAP efficiency. Wake-promoting medications are available where clinically appropriate.

Long-term studies are needed to confirm the CV safety of current wake-promoting medications. Real-world population-based studies on the effects of treatments on reducing car accidents and CV events (e.g., stroke, hypertension), as well as improving QoL, are also needed. In addition, evidence-based guidelines providing recommendations for the management of REDS and outlining the role of cardiologists in a multidisciplinary team are needed.

Funding. Funding for this manuscript and the journal's Rapid Service Fee was provided by Jazz Pharmaceuticals through an unrestricted educational grant. Jazz Pharmaceuticals had no control over the content and development of this manuscript.

Medical Writing and Editorial Assistance. Andrea Bothwell of inScience Communications (New York, NY, USA) and Elizabeth Samander of Springer Healthcare (New York, NY, USA) provided medical writing support. Brad Zerlanko of Springer Healthcare (Jersey City, NJ, USA) provided editorial support. This assistance was funded by an unrestricted medical education grant from Jazz Pharmaceuticals (Palo Alto, CA, USA).

Authorship. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Contributions. The authors equally participated in the development of the manuscript, had full editorial control, reviewed and edited various drafts, and provided their final approval of all content and submission for publication.

Disclosures. Reena Mehra reports receiving National Institutes of Health funding support from the National Heart, Lung, and Blood Institute [U01HL125177, UG3HL140144] and the American Heart Association. She has also received funds for service on the American Board of Medicine Sleep Medicine Exam test writing committee, Associate Editor of the American Journal of Respiratory and Critical Care Medicine, and royalties from UpToDate. Raphael Heinzer is member of the medical advisory board of Dreem and Nightbalance (Philips). He has received speaker's fees from Resmed, Philips, and Inspire. Raphael Heinzer also receives grant support from Apnimed and received grant support from Ligue pulmonaire Suisse from 2018 through 2020. He is part of an adjudication committee of Nyxoah. Pablo Castillo has no financial disclosures to report.

Compliance with Ethics Guidelines. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Data Availability. Data sharing is not applicable to this article as no data sets were generated or analyzed for this review.

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Functional consequences of inadequate sleep in adolescents: a systematic review

Evaluation and treatment of children and adolescents with excessive daytime sleepiness

Continuous positive airway pressure reduces daytime sleepiness Neurol Ther in mild to moderate obstructive sleep apnoea: a meta-analysis

Prevalence of residual excessive sleepiness in CPAP-treated sleep apnoea patients: the French multicentre study

Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning

Predictors of residual sleepiness in adequately treated obstructive sleep apnoea patients

The effect of CPAP in normalizing daytime sleepiness, quality of life, and neurocognitive function in patients with moderate to severe OSA

Predictors of sleepiness in obstructive sleep apnoea at baseline and after 6 months of continuous positive airway pressure therapy

Training, knowledge, attitudes and practices of Canadian health care providers regarding sleep and sleep disorders in children

Primary care physicians' knowledge of sleep medicine and barriers to transfer of patients with sleep disorders. A cross-sectional study

Long-term intermittent hypoxia in mice: protracted hypersomnolence with oxidative injury to sleep-wake brain regions

NADPH oxidase mediates hypersomnolence and brain oxidative injury in a murine model of sleep apnea

Slow-wave activity surrounding stage N2 K-complexes and daytime function measured by psychomotor vigilance test in obstructive sleep apnea

Diurnal and nocturnal serum melatonin concentrations after treatment with continuous positive airway pressure in patients with obstructive sleep apnea

A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid b

Brain white matter changes in CPAP-treated obstructive sleep apnea patients with residual sleepiness

Neuropathological investigation of cell layer thickness and myelination in the hippocampus of people with obstructive sleep apnea

Mean oxygen saturation during sleep is related to specific brain atrophy pattern

Hypoxia and hypercapnia inhibit hypothalamic orexin neurons in rats

Cumulative effects of repetitive intermittent hypercapnic hypoxia on orexin in the developing piglet hypothalamus

Ventilatory chemoresponsiveness, narcolepsy-cataplexy and human leukocyte antigen DQB1*0602 status

Hypocretin-1 (orexin A) prevents the effects of hypoxia/hypercapnia and enhances the GABAergic pathway from the lateral paragigantocellular nucleus to cardiac vagal neurons in the nucleus ambiguus

Neuroprotective effect of orexin-A is mediated by an increase of hypoxia-inducible factor-1 activity in rat

Orexins protect neuronal cell cultures against hypoxic stress: an involvement of Akt signaling

Ventilatory long-term facilitation in mice can be observed during both sleep and wake periods and depends on orexin

but unsuspected restless legs syndrome in patients with sleep apnea

Associations of undiagnosed obstructive sleep apnea and excessive daytime sleepiness with depression: an Australian population study

Sleep duration and excessive daytime sleepiness are associated with obesity independent of diet and physical activity

Different diagnostic criteria for periodic leg movements in patients with obstructive sleep apnea after continuous positive airway pressure titration

Beck depression inventory

Sleep problems during the COVID-19 pandemic by population: a systematic review and meta-analysis

A systematic review of COVID-19 and obstructive sleep apnoea

Treatment-emergent central sleep apnea (complex sleep apnea)

The sleep-immune crosstalk in health and disease

Sleep deficiency and chronic pain: potential underlying mechanisms and clinical implications

Benzodiazepine pharmacology and central nervous system-mediated effects

Sleep attacks, daytime sleepiness, and dopamine agonists in Parkinson's disease

Treatment of comorbid obstructive sleep apnea by upper airway stimulation results in resolution of debilitating symptoms of restless legs syndrome

Periodic limb movement disorder (PLMD) and restless legs syndrome (RLS)

NCBI Bookshelf website

Beta blockers. NCBI Bookshelf website. StatPearls Publishing

Considerations for the appropriate use of skeletal muscle relaxants for the management of acute low back pain

Effects of exercise training and CPAP in patients with heart failure and OSA: a preliminary study

Scoring of hypersomnolence and fatigue in patients with obstructive sleep apnea treated with a titratable custom-made mandibular advancement device

Mandibular advancement device and CPAP upon cardiovascular parameters in OSA

Treatment of upper airway resistance syndrome in adults: where do we stand?

Differences in clinical features of upper airway resistance syndrome, primary snoring, and obstructive sleep apnea/hypopnea syndrome

A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale

The Epworth Sleepiness Scale: validation of one-dimensional factor structure in a large clinical sample

Psychometric properties of the Epworth Sleepiness Scale: a factor analysis and itemresponse theory approach

The economic and societal burden of excessive daytime sleepiness in patients with obstructive sleep apnea

Screening and evaluation tools for sleep disorders in older adults

Comparison of subjective and objective assessments of sleep in healthy older subjects without sleep complaints

Practice parameters for clinical use of the Multiple Sleep Latency Test and the Maintenance of Wakefulness Test

Comparison of the oxford sleep resistance test and the multiple sleep latency test

PROVIGIL Ò (modafinil) tablets [prescribing information

NUVIGIL Ò (armodafinil) tablets [prescribing information

European Medicines Agency recommends restricting the use of modafinil. European Medicines Agency website

Pitolisant for daytime sleepiness in patients with obstructive sleep apnea who refuse continuous positive airway pressure treatment. A randomized trial

Pitolisant for residual excessive daytime sleepiness in OSA patients adhering to CPAP: a randomized trial

Solriamfetol for excessive sleepiness in obstructive sleep apnea (TONES 3). A randomized controlled trial

Modafinil/armodafinil in obstructive sleep apnoea: a systematic review and meta-analysis

SUNOSI TM (solriamfetol) tablets

Sunosi film-coated tablets (solriamfetol)

Profile of solriamfetol in the management of excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea: focus on patient selection and perspectives

649 in patients with OSA, still complaining of EDS and refusing to be treated by CPAP (HAROSA2)

BF2.649) in the treatment of excessive daytime sleepiness in patients with obstructive sleep apnoea syndrome, treated or not by nasal continuous positive airway pressure, but still complaining of excessive daytime sleepiness

AdisInsight Drugs website

Vom Nachrichtendienst. Bioprojet. Excessive daytime sleepiness in obstructive sleep apnoea syndrome: favourable opinion from the European Medicines Agency for Ozawade TM . CISION Ò PR Newswire website

Recently approved and upcoming treatments for narcolepsy

Study of TAK-925 in participants with obstructive sleep apnea (OSA) who are experiencing excessive daytime sleepiness (EDS) despite adequate use of continuous positive airway pressure (CPAP)

Fatigue assessment scale (FAS)

Using the fatigue severity scale to inform healthcare decision-making in multiple sclerosis: mapping to three quality-adjusted life-year measures (EQ5D-3L, SF-6D, MSIS-8D)

Evaluation of the PHQ-9 item 3 as a screen for sleep disturbance in primary care

Beck Depression Inventory-Fast Screen (BDI-FS): an efficient tool for depression screening in patients with end-stage renal disease

The clinical use of the MSLT and MWT

Obstructive sleep apnea devices for out-of-center (OOC) testing: technology evaluation

Modafinil as a catecholaminergic agent: empirical evidence and unanswered questions

Modafinil and the risk of cardiovascular events: findings from three US claims databases

A randomized, double-blind, placebo-and positive-controlled, 4-period crossover study of the effects of solriamfetol on QTcF intervals in healthy participants

Long-term study of the safety and maintenance of efficacy of solriamfetol (JZP-110) in the treatment of excessive sleepiness in participants with narcolepsy or obstructive sleep apnea