Sleep Strategies

The American Academy of Sleep Medicine recently published its position statement reaffirming its support of utilizing permanent Standard Time (ST) as opposed to Daylight Saving Time (DST).¹ DST usually occurs on the second Sunday in March when we “spring forward” by advancing the clock by 1 hour. The analogous “fall back” on the first Sunday in November refers to reversion back to the original ST, which is more synchronous with the sun’s natural pattern of rise and fall.

Arora_Subodh.jpg

The earliest argument for DST practice dates back to the 1700s when Benjamin Franklin wrote a satirical piece in the Journal of Paris suggesting that advancing the clock to rise earlier in the summer would lead to economization in candle usage and save significant resources for Parisians. The modern version of this assertion infers that increased daylight in the evening will lead to increased consumer activity and work productivity with consequent economic benefits. Interestingly, the adoption of DST has demonstrated the opposite—a reduction in work productivity and economic losses.² Another often-cited claim is that increased daylight in the evening could lead to fewer motor vehicle accidents. However, the reality is that DST is associated with more frequent car accidents in the morning.

The greatest drawback of DST is that, initially, it leads to sleep deprivation and chronically drives asynchronization between the circadian clock and the social clock. Humans synchronize their internal clock based on several factors, including light, temperature, feeding, and social habits. However, light is the strongest exogenous factor that regulates the internal clock. Light inhibits secretion of melatonin, an endogenous hormone that promotes sleep onset. While there is some individual variation in circadian patterns, exposure to bright light in the morning leads to increased physical, mental, and goal-directed activity.

Conversely, darkness or reduced light exposure in the evening hours promotes decreased activity and sleep onset via melatonin release. DST disrupts this natural process by promoting increased light exposure in the evening. This desynchronizes solar light from our internal clocks, causing a relative phase delay. Acutely, patients experience a form of imposed social jet lag. They lose an hour of sleep due to diminished sleep opportunity, as work and social obligations are typically not altered to allow for a later awakening. With recurrent delays, this lends to a pattern of chronic sleep deprivation which has significant health consequences.

Losing an hour of sleep opportunity as the clock advances in spring has dire consequences. The transition to DST is associated with increased cardiovascular events, including myocardial infarction, stroke, and admissions for acute atrial fibrillation.^{3 4 5} A large body of work has shown that acute reduction of sleep is associated with higher sympathetic tone, compromised immunity, and increased inflammation. Further, cognitive consequences can ensue in the form of altered situational awareness, increased risky behavior, and worse reaction time—which manifest as increased motor vehicle accidents, injuries, and fatalities.⁶ Emergency room visits and bounce-back admissions, medical errors and injuries, and missed appointments increase following the switch to DST.⁷ Psychiatric outcomes, including deaths due to suicide and overdose, are worse with the spring transition.⁸

Creamer_Jennifer.jpg

Is the problem with DST merely limited to springtime, when we lose an hour of sleep? Not quite. During the “fall back” period, despite theoretically gaining an hour of sleep opportunity, people exhibit evidence of sleep disruption, psychiatric issues, traffic accidents, and inflammatory bowel disease exacerbations. These consequences likely stem from a discordance between circadian and social time, which leads to an earlier awakening based on circadian physiology as opposed to the clock time.

The acute impact of changing our sleep patterns during transitions in clock time may be appreciated more readily, but the damage is much more insidious. Chronic exposure to light in the late evening creates a state of enhanced arousal when the body should be winding down. The chronic incongruency between clock and solar time leads to dyssynchrony in our usual functions, such as food intake, social and physical activity, and basal temperature. Consequently, there is an impetus to fall asleep later. This leads to an accumulation of sleep debt and its associated negative consequences in the general, already chronically sleep-deprived population. This is especially impactful to adolescents and young adults who tend to have a delay in their sleep and wake patterns and, yet, are socially bound to early morning awakenings for school or work.

The scientific evidence behind the health risk and benefit profile of DST and ST is incontrovertible and in favor of ST. The hallmark of appropriate sleep habits involves consistency and appropriate duration. Changing timing forward or backward increases the likelihood of an alteration of the baseline established sleep and circadian consistency.

Unfortunately, despite multiple polls demonstrating the populace’s dislike of DST, repeat attempts to codify DST and negate ST persist. The latest initiative, the Sunshine Protection Act, which promised permanent DST, was passed by the US Senate but was thankfully foiled by Congress in 2022. The act of setting a time is not one that should be taken lightly or in isolation because there are significant, long-lasting health, safety, and socioeconomic consequences of this decision. Practically, this entails a concerted effort from all major economies since consistency is essential for trade and geopolitical relations. China, Japan, and India don’t practice DST. The European Parliament voted successfully to abolish DST in the European Union in 2019 with a plan to implement ST in 2021. Implementation has yet to be successful due to interruptions from the COVID-19 pandemic as well as the current economic and political climate in Europe. Political or theoretical political victories should not supersede the health and safety of an elected official’s constituents. As a medical community, we should continue to use our collective voice to encourage our representatives to vote in ways that positively affect our patients’ health outcomes.

References:

1. Rishi MA, et al. JCSM. 2024;20(1):121.

2. Gibson M, et al. Rev Econ Stat. 2018;100(5):783.

3. Jansky I, et al. N Engl J Med. 2008;359(18):1966.

4. Sipilia J, et al. Sleep Med. 2016;27-28:20.

5. Chudow JJ, et al. Sleep Med. 2020;69:155.

6. Fritz J, et al. Curr Biol. 2020;30(4):729.

7. Ferrazzi E, et al. J Biol Rhythms. 2018;33(5):555-564.

8. Berk M, et al. Sleep Biol Rhythms. 2008;6(1):22.

The American Academy of Sleep Medicine recently published its position statement reaffirming its support of utilizing permanent Standard Time (ST) as opposed to Daylight Saving Time (DST).¹ DST usually occurs on the second Sunday in March when we “spring forward” by advancing the clock by 1 hour. The analogous “fall back” on the first Sunday in November refers to reversion back to the original ST, which is more synchronous with the sun’s natural pattern of rise and fall.

Arora_Subodh.jpg

The earliest argument for DST practice dates back to the 1700s when Benjamin Franklin wrote a satirical piece in the Journal of Paris suggesting that advancing the clock to rise earlier in the summer would lead to economization in candle usage and save significant resources for Parisians. The modern version of this assertion infers that increased daylight in the evening will lead to increased consumer activity and work productivity with consequent economic benefits. Interestingly, the adoption of DST has demonstrated the opposite—a reduction in work productivity and economic losses.² Another often-cited claim is that increased daylight in the evening could lead to fewer motor vehicle accidents. However, the reality is that DST is associated with more frequent car accidents in the morning.

The greatest drawback of DST is that, initially, it leads to sleep deprivation and chronically drives asynchronization between the circadian clock and the social clock. Humans synchronize their internal clock based on several factors, including light, temperature, feeding, and social habits. However, light is the strongest exogenous factor that regulates the internal clock. Light inhibits secretion of melatonin, an endogenous hormone that promotes sleep onset. While there is some individual variation in circadian patterns, exposure to bright light in the morning leads to increased physical, mental, and goal-directed activity.

Conversely, darkness or reduced light exposure in the evening hours promotes decreased activity and sleep onset via melatonin release. DST disrupts this natural process by promoting increased light exposure in the evening. This desynchronizes solar light from our internal clocks, causing a relative phase delay. Acutely, patients experience a form of imposed social jet lag. They lose an hour of sleep due to diminished sleep opportunity, as work and social obligations are typically not altered to allow for a later awakening. With recurrent delays, this lends to a pattern of chronic sleep deprivation which has significant health consequences.

Losing an hour of sleep opportunity as the clock advances in spring has dire consequences. The transition to DST is associated with increased cardiovascular events, including myocardial infarction, stroke, and admissions for acute atrial fibrillation.^{3 4 5} A large body of work has shown that acute reduction of sleep is associated with higher sympathetic tone, compromised immunity, and increased inflammation. Further, cognitive consequences can ensue in the form of altered situational awareness, increased risky behavior, and worse reaction time—which manifest as increased motor vehicle accidents, injuries, and fatalities.⁶ Emergency room visits and bounce-back admissions, medical errors and injuries, and missed appointments increase following the switch to DST.⁷ Psychiatric outcomes, including deaths due to suicide and overdose, are worse with the spring transition.⁸

Creamer_Jennifer.jpg

Is the problem with DST merely limited to springtime, when we lose an hour of sleep? Not quite. During the “fall back” period, despite theoretically gaining an hour of sleep opportunity, people exhibit evidence of sleep disruption, psychiatric issues, traffic accidents, and inflammatory bowel disease exacerbations. These consequences likely stem from a discordance between circadian and social time, which leads to an earlier awakening based on circadian physiology as opposed to the clock time.

The acute impact of changing our sleep patterns during transitions in clock time may be appreciated more readily, but the damage is much more insidious. Chronic exposure to light in the late evening creates a state of enhanced arousal when the body should be winding down. The chronic incongruency between clock and solar time leads to dyssynchrony in our usual functions, such as food intake, social and physical activity, and basal temperature. Consequently, there is an impetus to fall asleep later. This leads to an accumulation of sleep debt and its associated negative consequences in the general, already chronically sleep-deprived population. This is especially impactful to adolescents and young adults who tend to have a delay in their sleep and wake patterns and, yet, are socially bound to early morning awakenings for school or work.

The scientific evidence behind the health risk and benefit profile of DST and ST is incontrovertible and in favor of ST. The hallmark of appropriate sleep habits involves consistency and appropriate duration. Changing timing forward or backward increases the likelihood of an alteration of the baseline established sleep and circadian consistency.

Unfortunately, despite multiple polls demonstrating the populace’s dislike of DST, repeat attempts to codify DST and negate ST persist. The latest initiative, the Sunshine Protection Act, which promised permanent DST, was passed by the US Senate but was thankfully foiled by Congress in 2022. The act of setting a time is not one that should be taken lightly or in isolation because there are significant, long-lasting health, safety, and socioeconomic consequences of this decision. Practically, this entails a concerted effort from all major economies since consistency is essential for trade and geopolitical relations. China, Japan, and India don’t practice DST. The European Parliament voted successfully to abolish DST in the European Union in 2019 with a plan to implement ST in 2021. Implementation has yet to be successful due to interruptions from the COVID-19 pandemic as well as the current economic and political climate in Europe. Political or theoretical political victories should not supersede the health and safety of an elected official’s constituents. As a medical community, we should continue to use our collective voice to encourage our representatives to vote in ways that positively affect our patients’ health outcomes.

References:

1. Rishi MA, et al. JCSM. 2024;20(1):121.

2. Gibson M, et al. Rev Econ Stat. 2018;100(5):783.

3. Jansky I, et al. N Engl J Med. 2008;359(18):1966.

4. Sipilia J, et al. Sleep Med. 2016;27-28:20.

5. Chudow JJ, et al. Sleep Med. 2020;69:155.

6. Fritz J, et al. Curr Biol. 2020;30(4):729.

7. Ferrazzi E, et al. J Biol Rhythms. 2018;33(5):555-564.

8. Berk M, et al. Sleep Biol Rhythms. 2008;6(1):22.

The American Academy of Sleep Medicine recently published its position statement reaffirming its support of utilizing permanent Standard Time (ST) as opposed to Daylight Saving Time (DST).¹ DST usually occurs on the second Sunday in March when we “spring forward” by advancing the clock by 1 hour. The analogous “fall back” on the first Sunday in November refers to reversion back to the original ST, which is more synchronous with the sun’s natural pattern of rise and fall.

Arora_Subodh.jpg

The earliest argument for DST practice dates back to the 1700s when Benjamin Franklin wrote a satirical piece in the Journal of Paris suggesting that advancing the clock to rise earlier in the summer would lead to economization in candle usage and save significant resources for Parisians. The modern version of this assertion infers that increased daylight in the evening will lead to increased consumer activity and work productivity with consequent economic benefits. Interestingly, the adoption of DST has demonstrated the opposite—a reduction in work productivity and economic losses.² Another often-cited claim is that increased daylight in the evening could lead to fewer motor vehicle accidents. However, the reality is that DST is associated with more frequent car accidents in the morning.

The greatest drawback of DST is that, initially, it leads to sleep deprivation and chronically drives asynchronization between the circadian clock and the social clock. Humans synchronize their internal clock based on several factors, including light, temperature, feeding, and social habits. However, light is the strongest exogenous factor that regulates the internal clock. Light inhibits secretion of melatonin, an endogenous hormone that promotes sleep onset. While there is some individual variation in circadian patterns, exposure to bright light in the morning leads to increased physical, mental, and goal-directed activity.

Conversely, darkness or reduced light exposure in the evening hours promotes decreased activity and sleep onset via melatonin release. DST disrupts this natural process by promoting increased light exposure in the evening. This desynchronizes solar light from our internal clocks, causing a relative phase delay. Acutely, patients experience a form of imposed social jet lag. They lose an hour of sleep due to diminished sleep opportunity, as work and social obligations are typically not altered to allow for a later awakening. With recurrent delays, this lends to a pattern of chronic sleep deprivation which has significant health consequences.

Losing an hour of sleep opportunity as the clock advances in spring has dire consequences. The transition to DST is associated with increased cardiovascular events, including myocardial infarction, stroke, and admissions for acute atrial fibrillation.^{3 4 5} A large body of work has shown that acute reduction of sleep is associated with higher sympathetic tone, compromised immunity, and increased inflammation. Further, cognitive consequences can ensue in the form of altered situational awareness, increased risky behavior, and worse reaction time—which manifest as increased motor vehicle accidents, injuries, and fatalities.⁶ Emergency room visits and bounce-back admissions, medical errors and injuries, and missed appointments increase following the switch to DST.⁷ Psychiatric outcomes, including deaths due to suicide and overdose, are worse with the spring transition.⁸

Creamer_Jennifer.jpg

Is the problem with DST merely limited to springtime, when we lose an hour of sleep? Not quite. During the “fall back” period, despite theoretically gaining an hour of sleep opportunity, people exhibit evidence of sleep disruption, psychiatric issues, traffic accidents, and inflammatory bowel disease exacerbations. These consequences likely stem from a discordance between circadian and social time, which leads to an earlier awakening based on circadian physiology as opposed to the clock time.

The acute impact of changing our sleep patterns during transitions in clock time may be appreciated more readily, but the damage is much more insidious. Chronic exposure to light in the late evening creates a state of enhanced arousal when the body should be winding down. The chronic incongruency between clock and solar time leads to dyssynchrony in our usual functions, such as food intake, social and physical activity, and basal temperature. Consequently, there is an impetus to fall asleep later. This leads to an accumulation of sleep debt and its associated negative consequences in the general, already chronically sleep-deprived population. This is especially impactful to adolescents and young adults who tend to have a delay in their sleep and wake patterns and, yet, are socially bound to early morning awakenings for school or work.

The scientific evidence behind the health risk and benefit profile of DST and ST is incontrovertible and in favor of ST. The hallmark of appropriate sleep habits involves consistency and appropriate duration. Changing timing forward or backward increases the likelihood of an alteration of the baseline established sleep and circadian consistency.

Unfortunately, despite multiple polls demonstrating the populace’s dislike of DST, repeat attempts to codify DST and negate ST persist. The latest initiative, the Sunshine Protection Act, which promised permanent DST, was passed by the US Senate but was thankfully foiled by Congress in 2022. The act of setting a time is not one that should be taken lightly or in isolation because there are significant, long-lasting health, safety, and socioeconomic consequences of this decision. Practically, this entails a concerted effort from all major economies since consistency is essential for trade and geopolitical relations. China, Japan, and India don’t practice DST. The European Parliament voted successfully to abolish DST in the European Union in 2019 with a plan to implement ST in 2021. Implementation has yet to be successful due to interruptions from the COVID-19 pandemic as well as the current economic and political climate in Europe. Political or theoretical political victories should not supersede the health and safety of an elected official’s constituents. As a medical community, we should continue to use our collective voice to encourage our representatives to vote in ways that positively affect our patients’ health outcomes.

References:

1. Rishi MA, et al. JCSM. 2024;20(1):121.

2. Gibson M, et al. Rev Econ Stat. 2018;100(5):783.

3. Jansky I, et al. N Engl J Med. 2008;359(18):1966.

4. Sipilia J, et al. Sleep Med. 2016;27-28:20.

5. Chudow JJ, et al. Sleep Med. 2020;69:155.

6. Fritz J, et al. Curr Biol. 2020;30(4):729.

7. Ferrazzi E, et al. J Biol Rhythms. 2018;33(5):555-564.

8. Berk M, et al. Sleep Biol Rhythms. 2008;6(1):22.

Residual excessive daytime sleepiness (REDS) is defined as the urge to sleep during the day despite an intention to remain alert after optimal treatment of obstructive sleep apnea (OSA). This is a distressing outcome with an estimated prevalence of 9% to 22% among patients with OSA (Pépin JL, et al. Eur Respir J. 2009;33[5]:1062). The pathophysiology of the condition is complex, and experimental studies conducted on animal models have demonstrated that chronic sleep fragmentation and chronic intermittent hypoxia can result in detrimental effects on wake-­promoting neurons. Additionally, there is evidence of heightened oxidative stress and alterations in melatonin secretion, with the severity and duration of the disease playing a significant role in the manifestation of these effects (Javaheri S, et al. Chest. 2020;158[2]:776). It is considered a diagnosis of exclusion, with the assessment being mostly subjective. Prior to diagnosing REDS, it is crucial to optimize positive airway pressure (PAP) therapy and nocturnal ventilation, ensure sufficient adherence to sleep hygiene practices, and exclude the presence of other sleep disorders. The Epworth Sleepiness Scale (ESS) score is widely utilized as a primary clinical tool in the assessment of sleepiness. To enhance the precision of this score, it is advantageous to take input from both family members and friends. Additional objective assessments that could be considered include the utilization of the Multiple Sleep Latency Test (MSLT) or the Maintenance of Wakefulness Test (MWT).

Mechineni_Ashesha_web.jpg

Due to the socioeconomic and public health considerations of REDS, pharmacological therapy is crucial to its management after exhausting conservative measures. Off-label use of traditional central nervous system stimulants, like amphetamine or methylphenidate, in these patients is almost extinct. The potential for abuse and negative consequences outweighs the potential benefits. FDA-approved medications for treatment of REDS in OSA include modafinil, armodafinil, and solriamfetol in the United States.

Sahni_Ashima_web.jpg

Historically, modafinil and armodafinil are the first-line and most commonly used wake-promoting agents. Both agents bind to the dopamine transporter and inhibit dopamine reuptake. They have demonstrated efficacy in reducing EDS and improving wakefulness in patients with OSA treated with CPAP. A meta-analysis of 10 randomized, placebo-controlled trials of modafinil and armodafinil found that they were better than placebo by 2.2 points on the ESS score and 3 minutes on the MWT (Maintenance of Wakefulness Test) (Chapman JL, et al. Eur Respir J. 2016;47[5]:1420). Both drugs have common adverse effects of headache, nausea, nervousness, insomnia, dizziness, rhinitis, and diarrhea. Drug interaction with CYP3A4/5 substrates and oral contraceptives is a concern with these medications. In 2010, the European Medicines Agency restricted the use of modafinil only to patients with narcolepsy, considering its cardiovascular and neuropsychiatric risks (European Medicines Agency website; press release, July 22, 2010).

Solriamfetol is the newest medication being utilized for EDS in OSA and is approved in both the United States and Europe for this indication. It is a dopamine and norepinephrine reuptake inhibitor with a simultaneous effect on both transporters. It has been effective in improving wakefulness and reducing sleepiness in patients with residual OSA. In the landmark trial TONES 3, dose-dependent (37.5, 75, 150, and 300 mg/day) effects were observed, with improvements in ESS scores of –1.9 to –4.7 points and sleep latency in MWT by 4.5 to 12.8 minutes (Schweitzer PK, et al. Am J Respir Crit Care Med. 2019;199[11]:1421). The current recommended dosing for REDS in OSA is to start with the lowest dose of 37.5 mg/day and increase to the maximum dose of 150 mg/day by titrating up every 3 days if needed. A recent meta-analysis showed an indirect treatment comparison between efficacy and safety among the medications solriamfetol, modafinil, and armodafinil (Ronnebaum S, et al. J Clin Sleep Med. 2021;17[12]:2543). Six parallel-arm, placebo-controlled, randomized, controlled trials were looked at. The ESS score, MWT20 sleep latency, and CGI-C (Clinical Global Impression of Change) all got better in comparison to the placebo. Relative to the comparators and placebo at 12 weeks, solriamfetol at 150 mg and 300 mg had the highest degree of improvement in all the outcomes studied. Common adverse effects of solriamfetol include headache, nausea, decreased appetite, insomnia, dry mouth, anxiety, and minimal increase in blood pressure and heart rate. The adverse effects in terms of blood pressure and heart rate change have a dose-dependent relationship, and serial vitals monitoring is recommended for patients every 6 months to a year. This medication is contraindicated in patients receiving concomitant monoamine oxidase inhibitors (MAOIs) or within 14 days following discontinuation of an MAOI because of the risk of hypertensive reactions. Solriamfetol is renally excreted, so dose adjustment is needed in patients with moderate to severe renal impairment. It is not recommended for use in end-stage renal disease (eGFR <15 mL/min/1.73 m²) (SUNOSI. Full prescribing information. Axsome; revised 06/2023. https://www.sunosihcp.com/assets/files/sunosi.en.uspi.pdf. Accessed: Sept 24, 2023). Solriamfetol demonstrates a comparatively shorter half-life when compared with traditional pharmaceuticals like modafinil and armodafinil, implying the possibility of a decreased duration of its effects. The effect in question may exhibit interpersonal diversity in its impact on quality of life when applied in a therapeutic setting.

Pitolisant is another potential medication to treat REDS in patients with OSA. While only approved for treating EDS and cataplexy in adult US patients with narcolepsy, it is currently approved for REDS in OSA in Europe (Ozawade. European Medicines Agency. Last updated 12/05/2022. https://www.ema.europa.eu/en/medicines/human/EPAR/ozawade#product-information-­section. Accessed: Oct 2, 2023). It is a selective histamine H3 receptor antagonist and an inverse agonist of the presynaptic H3 receptor. The fact that this medication is not scheduled and has a negligible or nonexistent risk of abuse is one of its advantages. It is dosed once daily, and the most frequent adverse effects include headaches and insomnia. A prolonged QT interval was observed in a few patients; caution is needed with concomitant use of other medications with known similar effects. Dosage modification is recommended in patients with moderate hepatic impairment and moderate to severe renal impairment. Drug interactions are also observed with the concomitant use of CYP2D6 inhibitors and CYP3A4 inducers. Pitolisant may reduce the efficacy of hormonal contraception, including up to 21 days after its discontinuation (WAKIX. Full prescribing information. Harmony biosciences; revised 12/2022.https://wakixhcp.com/pdf/wakix-­tablets-pi.pdf. Accessed: Sept 24, 2023).
 

Dr. Mechineni is Sleep Attending Physician, Ascension Illinois, Alexian Brothers Medical Center, Chicago. Dr. Sahni is Assistant Professor of Clinical Medicine, Associate Program Director, Sleep Medicine Fellowship; Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago.

Residual excessive daytime sleepiness (REDS) is defined as the urge to sleep during the day despite an intention to remain alert after optimal treatment of obstructive sleep apnea (OSA). This is a distressing outcome with an estimated prevalence of 9% to 22% among patients with OSA (Pépin JL, et al. Eur Respir J. 2009;33[5]:1062). The pathophysiology of the condition is complex, and experimental studies conducted on animal models have demonstrated that chronic sleep fragmentation and chronic intermittent hypoxia can result in detrimental effects on wake-­promoting neurons. Additionally, there is evidence of heightened oxidative stress and alterations in melatonin secretion, with the severity and duration of the disease playing a significant role in the manifestation of these effects (Javaheri S, et al. Chest. 2020;158[2]:776). It is considered a diagnosis of exclusion, with the assessment being mostly subjective. Prior to diagnosing REDS, it is crucial to optimize positive airway pressure (PAP) therapy and nocturnal ventilation, ensure sufficient adherence to sleep hygiene practices, and exclude the presence of other sleep disorders. The Epworth Sleepiness Scale (ESS) score is widely utilized as a primary clinical tool in the assessment of sleepiness. To enhance the precision of this score, it is advantageous to take input from both family members and friends. Additional objective assessments that could be considered include the utilization of the Multiple Sleep Latency Test (MSLT) or the Maintenance of Wakefulness Test (MWT).

Mechineni_Ashesha_web.jpg

Due to the socioeconomic and public health considerations of REDS, pharmacological therapy is crucial to its management after exhausting conservative measures. Off-label use of traditional central nervous system stimulants, like amphetamine or methylphenidate, in these patients is almost extinct. The potential for abuse and negative consequences outweighs the potential benefits. FDA-approved medications for treatment of REDS in OSA include modafinil, armodafinil, and solriamfetol in the United States.

Sahni_Ashima_web.jpg

Historically, modafinil and armodafinil are the first-line and most commonly used wake-promoting agents. Both agents bind to the dopamine transporter and inhibit dopamine reuptake. They have demonstrated efficacy in reducing EDS and improving wakefulness in patients with OSA treated with CPAP. A meta-analysis of 10 randomized, placebo-controlled trials of modafinil and armodafinil found that they were better than placebo by 2.2 points on the ESS score and 3 minutes on the MWT (Maintenance of Wakefulness Test) (Chapman JL, et al. Eur Respir J. 2016;47[5]:1420). Both drugs have common adverse effects of headache, nausea, nervousness, insomnia, dizziness, rhinitis, and diarrhea. Drug interaction with CYP3A4/5 substrates and oral contraceptives is a concern with these medications. In 2010, the European Medicines Agency restricted the use of modafinil only to patients with narcolepsy, considering its cardiovascular and neuropsychiatric risks (European Medicines Agency website; press release, July 22, 2010).

Solriamfetol is the newest medication being utilized for EDS in OSA and is approved in both the United States and Europe for this indication. It is a dopamine and norepinephrine reuptake inhibitor with a simultaneous effect on both transporters. It has been effective in improving wakefulness and reducing sleepiness in patients with residual OSA. In the landmark trial TONES 3, dose-dependent (37.5, 75, 150, and 300 mg/day) effects were observed, with improvements in ESS scores of –1.9 to –4.7 points and sleep latency in MWT by 4.5 to 12.8 minutes (Schweitzer PK, et al. Am J Respir Crit Care Med. 2019;199[11]:1421). The current recommended dosing for REDS in OSA is to start with the lowest dose of 37.5 mg/day and increase to the maximum dose of 150 mg/day by titrating up every 3 days if needed. A recent meta-analysis showed an indirect treatment comparison between efficacy and safety among the medications solriamfetol, modafinil, and armodafinil (Ronnebaum S, et al. J Clin Sleep Med. 2021;17[12]:2543). Six parallel-arm, placebo-controlled, randomized, controlled trials were looked at. The ESS score, MWT20 sleep latency, and CGI-C (Clinical Global Impression of Change) all got better in comparison to the placebo. Relative to the comparators and placebo at 12 weeks, solriamfetol at 150 mg and 300 mg had the highest degree of improvement in all the outcomes studied. Common adverse effects of solriamfetol include headache, nausea, decreased appetite, insomnia, dry mouth, anxiety, and minimal increase in blood pressure and heart rate. The adverse effects in terms of blood pressure and heart rate change have a dose-dependent relationship, and serial vitals monitoring is recommended for patients every 6 months to a year. This medication is contraindicated in patients receiving concomitant monoamine oxidase inhibitors (MAOIs) or within 14 days following discontinuation of an MAOI because of the risk of hypertensive reactions. Solriamfetol is renally excreted, so dose adjustment is needed in patients with moderate to severe renal impairment. It is not recommended for use in end-stage renal disease (eGFR <15 mL/min/1.73 m²) (SUNOSI. Full prescribing information. Axsome; revised 06/2023. https://www.sunosihcp.com/assets/files/sunosi.en.uspi.pdf. Accessed: Sept 24, 2023). Solriamfetol demonstrates a comparatively shorter half-life when compared with traditional pharmaceuticals like modafinil and armodafinil, implying the possibility of a decreased duration of its effects. The effect in question may exhibit interpersonal diversity in its impact on quality of life when applied in a therapeutic setting.

Pitolisant is another potential medication to treat REDS in patients with OSA. While only approved for treating EDS and cataplexy in adult US patients with narcolepsy, it is currently approved for REDS in OSA in Europe (Ozawade. European Medicines Agency. Last updated 12/05/2022. https://www.ema.europa.eu/en/medicines/human/EPAR/ozawade#product-information-­section. Accessed: Oct 2, 2023). It is a selective histamine H3 receptor antagonist and an inverse agonist of the presynaptic H3 receptor. The fact that this medication is not scheduled and has a negligible or nonexistent risk of abuse is one of its advantages. It is dosed once daily, and the most frequent adverse effects include headaches and insomnia. A prolonged QT interval was observed in a few patients; caution is needed with concomitant use of other medications with known similar effects. Dosage modification is recommended in patients with moderate hepatic impairment and moderate to severe renal impairment. Drug interactions are also observed with the concomitant use of CYP2D6 inhibitors and CYP3A4 inducers. Pitolisant may reduce the efficacy of hormonal contraception, including up to 21 days after its discontinuation (WAKIX. Full prescribing information. Harmony biosciences; revised 12/2022.https://wakixhcp.com/pdf/wakix-­tablets-pi.pdf. Accessed: Sept 24, 2023).
 

Dr. Mechineni is Sleep Attending Physician, Ascension Illinois, Alexian Brothers Medical Center, Chicago. Dr. Sahni is Assistant Professor of Clinical Medicine, Associate Program Director, Sleep Medicine Fellowship; Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago.

Residual excessive daytime sleepiness (REDS) is defined as the urge to sleep during the day despite an intention to remain alert after optimal treatment of obstructive sleep apnea (OSA). This is a distressing outcome with an estimated prevalence of 9% to 22% among patients with OSA (Pépin JL, et al. Eur Respir J. 2009;33[5]:1062). The pathophysiology of the condition is complex, and experimental studies conducted on animal models have demonstrated that chronic sleep fragmentation and chronic intermittent hypoxia can result in detrimental effects on wake-­promoting neurons. Additionally, there is evidence of heightened oxidative stress and alterations in melatonin secretion, with the severity and duration of the disease playing a significant role in the manifestation of these effects (Javaheri S, et al. Chest. 2020;158[2]:776). It is considered a diagnosis of exclusion, with the assessment being mostly subjective. Prior to diagnosing REDS, it is crucial to optimize positive airway pressure (PAP) therapy and nocturnal ventilation, ensure sufficient adherence to sleep hygiene practices, and exclude the presence of other sleep disorders. The Epworth Sleepiness Scale (ESS) score is widely utilized as a primary clinical tool in the assessment of sleepiness. To enhance the precision of this score, it is advantageous to take input from both family members and friends. Additional objective assessments that could be considered include the utilization of the Multiple Sleep Latency Test (MSLT) or the Maintenance of Wakefulness Test (MWT).

Mechineni_Ashesha_web.jpg

Due to the socioeconomic and public health considerations of REDS, pharmacological therapy is crucial to its management after exhausting conservative measures. Off-label use of traditional central nervous system stimulants, like amphetamine or methylphenidate, in these patients is almost extinct. The potential for abuse and negative consequences outweighs the potential benefits. FDA-approved medications for treatment of REDS in OSA include modafinil, armodafinil, and solriamfetol in the United States.

Sahni_Ashima_web.jpg

Historically, modafinil and armodafinil are the first-line and most commonly used wake-promoting agents. Both agents bind to the dopamine transporter and inhibit dopamine reuptake. They have demonstrated efficacy in reducing EDS and improving wakefulness in patients with OSA treated with CPAP. A meta-analysis of 10 randomized, placebo-controlled trials of modafinil and armodafinil found that they were better than placebo by 2.2 points on the ESS score and 3 minutes on the MWT (Maintenance of Wakefulness Test) (Chapman JL, et al. Eur Respir J. 2016;47[5]:1420). Both drugs have common adverse effects of headache, nausea, nervousness, insomnia, dizziness, rhinitis, and diarrhea. Drug interaction with CYP3A4/5 substrates and oral contraceptives is a concern with these medications. In 2010, the European Medicines Agency restricted the use of modafinil only to patients with narcolepsy, considering its cardiovascular and neuropsychiatric risks (European Medicines Agency website; press release, July 22, 2010).

Solriamfetol is the newest medication being utilized for EDS in OSA and is approved in both the United States and Europe for this indication. It is a dopamine and norepinephrine reuptake inhibitor with a simultaneous effect on both transporters. It has been effective in improving wakefulness and reducing sleepiness in patients with residual OSA. In the landmark trial TONES 3, dose-dependent (37.5, 75, 150, and 300 mg/day) effects were observed, with improvements in ESS scores of –1.9 to –4.7 points and sleep latency in MWT by 4.5 to 12.8 minutes (Schweitzer PK, et al. Am J Respir Crit Care Med. 2019;199[11]:1421). The current recommended dosing for REDS in OSA is to start with the lowest dose of 37.5 mg/day and increase to the maximum dose of 150 mg/day by titrating up every 3 days if needed. A recent meta-analysis showed an indirect treatment comparison between efficacy and safety among the medications solriamfetol, modafinil, and armodafinil (Ronnebaum S, et al. J Clin Sleep Med. 2021;17[12]:2543). Six parallel-arm, placebo-controlled, randomized, controlled trials were looked at. The ESS score, MWT20 sleep latency, and CGI-C (Clinical Global Impression of Change) all got better in comparison to the placebo. Relative to the comparators and placebo at 12 weeks, solriamfetol at 150 mg and 300 mg had the highest degree of improvement in all the outcomes studied. Common adverse effects of solriamfetol include headache, nausea, decreased appetite, insomnia, dry mouth, anxiety, and minimal increase in blood pressure and heart rate. The adverse effects in terms of blood pressure and heart rate change have a dose-dependent relationship, and serial vitals monitoring is recommended for patients every 6 months to a year. This medication is contraindicated in patients receiving concomitant monoamine oxidase inhibitors (MAOIs) or within 14 days following discontinuation of an MAOI because of the risk of hypertensive reactions. Solriamfetol is renally excreted, so dose adjustment is needed in patients with moderate to severe renal impairment. It is not recommended for use in end-stage renal disease (eGFR <15 mL/min/1.73 m²) (SUNOSI. Full prescribing information. Axsome; revised 06/2023. https://www.sunosihcp.com/assets/files/sunosi.en.uspi.pdf. Accessed: Sept 24, 2023). Solriamfetol demonstrates a comparatively shorter half-life when compared with traditional pharmaceuticals like modafinil and armodafinil, implying the possibility of a decreased duration of its effects. The effect in question may exhibit interpersonal diversity in its impact on quality of life when applied in a therapeutic setting.

Pitolisant is another potential medication to treat REDS in patients with OSA. While only approved for treating EDS and cataplexy in adult US patients with narcolepsy, it is currently approved for REDS in OSA in Europe (Ozawade. European Medicines Agency. Last updated 12/05/2022. https://www.ema.europa.eu/en/medicines/human/EPAR/ozawade#product-information-­section. Accessed: Oct 2, 2023). It is a selective histamine H3 receptor antagonist and an inverse agonist of the presynaptic H3 receptor. The fact that this medication is not scheduled and has a negligible or nonexistent risk of abuse is one of its advantages. It is dosed once daily, and the most frequent adverse effects include headaches and insomnia. A prolonged QT interval was observed in a few patients; caution is needed with concomitant use of other medications with known similar effects. Dosage modification is recommended in patients with moderate hepatic impairment and moderate to severe renal impairment. Drug interactions are also observed with the concomitant use of CYP2D6 inhibitors and CYP3A4 inducers. Pitolisant may reduce the efficacy of hormonal contraception, including up to 21 days after its discontinuation (WAKIX. Full prescribing information. Harmony biosciences; revised 12/2022.https://wakixhcp.com/pdf/wakix-­tablets-pi.pdf. Accessed: Sept 24, 2023).
 

Dr. Mechineni is Sleep Attending Physician, Ascension Illinois, Alexian Brothers Medical Center, Chicago. Dr. Sahni is Assistant Professor of Clinical Medicine, Associate Program Director, Sleep Medicine Fellowship; Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago.

Sleep Medicine Network

Respiratory-Related Sleep Disorders Section

The overlap syndrome (OS), which refers to the co-occurrence of OSA and COPD, was first described by Flenley in 1985 (Flenley DC. Clin Chest Med. 1985;6[4]:651). Over the years, numerous studies have demonstrated an increased risk of hospitalization and mortality in patients with OS (Brennan M, et al. 2022;1-10). Despite these findings, limited evidence exists regarding the optimal treatment approach for individuals with OS.

Gill_Kirat_CALIF_web.jpg

CPAP therapy has demonstrated various physiologic advantages for patients with OS (Srivali N, et al. Sleep Med. 2023;108:55-60), which contribute to diminished dyspnea symptoms, lowered pro-inflammatory markers, improved arterial blood gases, increased 6-minute walk distance, enhanced FEV₁, and decreased mean pulmonary artery pressure (Suri TM, et al. FASEB BioAdv. 2021;3[9]:683-93). CPAP therapy in patients with OS has been linked to a reduction in COPD exacerbations (Voulgaris A, et al. Clin Respir Jour. 2023; 17[3]:165), fewer COPD-related hospitalizations (Marin JM, et al. Am J Respir Crit Care Med. 2010;182[3]:325-31), decreased cardiovascular events (Kendzerska T, et al. Ann ATS. 2019;16[1]:71), and an overall decline in mortality rates (Machado ML, et al. Eur Respir J. 2010;35[1]:132-7).

It is important to acknowledge that, as of now, no randomized clinical trial has specifically addressed the treatment of OS, leaving recommendations largely reliant on observational studies. Conversely, recent guidelines have proposed the utilization of high-intensity noninvasive ventilation (NIV) for hypercapnic patients with COPD. Thus, extensive research is warranted to characterize distinct sleep-related breathing disorders within the OS population and to investigate the effects of CPAP in comparison to other NIV modalities on patients with overlap syndrome.

Solmaz Ehteshami-Afshar, MD

Kirat Gill, MD, Section Member-at-Large

Sleep Medicine Network

Respiratory-Related Sleep Disorders Section

The overlap syndrome (OS), which refers to the co-occurrence of OSA and COPD, was first described by Flenley in 1985 (Flenley DC. Clin Chest Med. 1985;6[4]:651). Over the years, numerous studies have demonstrated an increased risk of hospitalization and mortality in patients with OS (Brennan M, et al. 2022;1-10). Despite these findings, limited evidence exists regarding the optimal treatment approach for individuals with OS.

Gill_Kirat_CALIF_web.jpg

CPAP therapy has demonstrated various physiologic advantages for patients with OS (Srivali N, et al. Sleep Med. 2023;108:55-60), which contribute to diminished dyspnea symptoms, lowered pro-inflammatory markers, improved arterial blood gases, increased 6-minute walk distance, enhanced FEV₁, and decreased mean pulmonary artery pressure (Suri TM, et al. FASEB BioAdv. 2021;3[9]:683-93). CPAP therapy in patients with OS has been linked to a reduction in COPD exacerbations (Voulgaris A, et al. Clin Respir Jour. 2023; 17[3]:165), fewer COPD-related hospitalizations (Marin JM, et al. Am J Respir Crit Care Med. 2010;182[3]:325-31), decreased cardiovascular events (Kendzerska T, et al. Ann ATS. 2019;16[1]:71), and an overall decline in mortality rates (Machado ML, et al. Eur Respir J. 2010;35[1]:132-7).

It is important to acknowledge that, as of now, no randomized clinical trial has specifically addressed the treatment of OS, leaving recommendations largely reliant on observational studies. Conversely, recent guidelines have proposed the utilization of high-intensity noninvasive ventilation (NIV) for hypercapnic patients with COPD. Thus, extensive research is warranted to characterize distinct sleep-related breathing disorders within the OS population and to investigate the effects of CPAP in comparison to other NIV modalities on patients with overlap syndrome.

Solmaz Ehteshami-Afshar, MD

Kirat Gill, MD, Section Member-at-Large

Sleep Medicine Network

Respiratory-Related Sleep Disorders Section

The overlap syndrome (OS), which refers to the co-occurrence of OSA and COPD, was first described by Flenley in 1985 (Flenley DC. Clin Chest Med. 1985;6[4]:651). Over the years, numerous studies have demonstrated an increased risk of hospitalization and mortality in patients with OS (Brennan M, et al. 2022;1-10). Despite these findings, limited evidence exists regarding the optimal treatment approach for individuals with OS.

Gill_Kirat_CALIF_web.jpg

CPAP therapy has demonstrated various physiologic advantages for patients with OS (Srivali N, et al. Sleep Med. 2023;108:55-60), which contribute to diminished dyspnea symptoms, lowered pro-inflammatory markers, improved arterial blood gases, increased 6-minute walk distance, enhanced FEV₁, and decreased mean pulmonary artery pressure (Suri TM, et al. FASEB BioAdv. 2021;3[9]:683-93). CPAP therapy in patients with OS has been linked to a reduction in COPD exacerbations (Voulgaris A, et al. Clin Respir Jour. 2023; 17[3]:165), fewer COPD-related hospitalizations (Marin JM, et al. Am J Respir Crit Care Med. 2010;182[3]:325-31), decreased cardiovascular events (Kendzerska T, et al. Ann ATS. 2019;16[1]:71), and an overall decline in mortality rates (Machado ML, et al. Eur Respir J. 2010;35[1]:132-7).

It is important to acknowledge that, as of now, no randomized clinical trial has specifically addressed the treatment of OS, leaving recommendations largely reliant on observational studies. Conversely, recent guidelines have proposed the utilization of high-intensity noninvasive ventilation (NIV) for hypercapnic patients with COPD. Thus, extensive research is warranted to characterize distinct sleep-related breathing disorders within the OS population and to investigate the effects of CPAP in comparison to other NIV modalities on patients with overlap syndrome.

Solmaz Ehteshami-Afshar, MD

Kirat Gill, MD, Section Member-at-Large

It is estimated that almost one billion people globally are affected by obstructive sleep apnea (OSA) (Benjafield A, et al. Lancet Respir Med. 2019;7[8]:687-98). Despite such high prevalence, the treatment options for OSA are somewhat limited. Continuous positive airway pressure (CPAP), the gold standard therapy, is not viable for many due to difficulties tolerating the device or mask, and thus may not be a realistic long-term solution. As per certain estimates, nearly 50% of CPAP users discontinue treatment by the fifth year (Schoch O, et al. Respiration. 2014;87[2]:121-8). Furthermore, alternative options such as mandibular advancement devices, positional therapy, weight loss, and maxillofacial or palate surgery, also have unique challenges and limitations.

Gill_Kirat_CALIF_web.jpg

First described in 2001, hypoglossal nerve stimulation (HGNS) is a relatively new and emerging technology for the treatment of OSA (Schwartz A, et al. Arch Otolaryngol Head Neck Surg. 2001 Oct;127[10]:1216-23). HGNS therapy was approved by the Food and Drug Administration in 2014 for the treatment of moderate to severe OSA. The therapy involves surgical implantation of the HGNS device, optimization of device settings, and evaluation for treatment response. A physician-led multidisciplinary Hypoglossal Nerve Stimulation Clinic involves collaboration from essential stakeholders, most importantly sleep medicine providers, clinic staff, sleep technologists, and ENT sleep surgeons. Goals of the multidisciplinary program are to ensure timely follow-up, optimization of device settings, and maximizing treatment efficacy. This review describes steps involved in developing a successful multidisciplinary HGNS program within a sleep medicine practice.
 

Patient selection and evaluation

There is growing interest in HGNS relative to conventional CPAP therapy, with many patients presenting to clinic to inquire about this therapy. However, not all patients are candidates for HGNS therapy. Prioritizing appropriate patient selection and education are key first steps. The initial assessments usually occur with a sleep medicine specialist. It begins with confirmation of the diagnosis of OSA in all patients and a concerted effort to troubleshoot and address any barriers to CPAP use before consideration of surgery. Patients who are unwilling to use or unable to tolerate CPAP therapy undergo further evaluation for HGNS therapy. It is important to ensure that patients are also screened for other sleep disorders, such as insomnia or restless leg syndrome, to rule out its contribution to daytime (or nighttime) symptoms.

Other salient inclusion criteria include an apnea-hypopnea index (AHI) between 15-100 events per hour (previously 65), at least 18 years of age, and a body mass index (BMI) less than 40 kg/m² (previously 32). Qualifying patients undergo an updated polysomnography if a recent study is not available. If the polysomnography reveals central and mixed apneas comprising less than 25 percent of the total AHI, patients are referred to ENT Sleep Surgery, and drug-induced sleep endoscopy is offered to examine upper airway anatomy. When a complete concentric collapse of the soft palate is seen on drug-induced sleep endoscopy, surgery is contraindicated. Prior palate surgery or maxillomandibular advancement (MMA) are not contraindications to HGNS therapy.

The patients receive comprehensive information on the nature of the surgery, expected recovery course, and device activation timeline. Perhaps most importantly, the patients receive structured education on HGNS therapy and potential outcomes to set realistic expectations. In the STAR trial, patients experienced a reduction in the AHI of approximately 70% (Strollo P, et al. N Engl J Med. 2014;370[2]:139-49). It is important to note that a response to therapy was defined as a reduction in the AHI by at least 50% and a value less than 20 events/hour (Strollo P, et al. Sleep. 2015;38[10]:1593-8). Therefore, patients who are expecting complete resolution of snoring and/or OSA may not be ideal candidates for surgery. Furthermore, patients who continue to experience fatigue and sleepiness on CPAP despite control of OSA may not experience amelioration of these symptoms with HGNS therapy.
 

Surgery and device management

The surgery, performed under general anesthesia, lasts approximately 3 hours, and may be followed by an overnight hospital stay depending on patient’s comorbidities. The device implantation involves placement of an implantable pulse generator (IPG) in the chest wall and leads to the hypoglossal nerve. The IPG is similar to a pacemaker and functions to stimulate the ipsilateral hypoglossal nerve innervating the tongue during sleep. The most common postoperative complications noted in the STAR trial data include incision site pain and swelling as well as temporary tongue weakness or paresthesia. Postoperative restrictions are minimal and include no heavy lifting for one month after surgery.

One week postsurgery, patients return to the ENT Sleep Surgery Clinic for follow-up, at which time the incisions as well as tongue strength and sensation are evaluated. In a subsequent visit between 4 and 6 weeks postsurgery, patients are evaluated in a joint Sleep Medicine and ENT clinic. They undergo device education and activation of the IPG using a dedicated programmer obtained from the device manufacturer. Device comfort features such as start delay and pause time are also programmed. Furthermore, appropriate tongue movement, lead placement, and voltage range settings are assessed during the visit. The ENT surgery team reevaluates the incision sites and assesses for tongue function and sensation. Patients are instructed to increase the voltage incrementally every week as tolerated with the goal of using the device nightly for the entirety of sleep. If patients tolerate the therapy well during the 2- to 3-month follow-up, a sleep study is scheduled to evaluate treatment effectiveness at the peak tolerable voltage. For those struggling with the therapy, adjustments to electrode configurations should be considered for pulse width, and rate. Occasionally, patients may require awake endoscopy and/or an advanced HGNS titration while asleep to determine the most appropriate settings to optimally control sleep apnea.

Until recently, patients implanted with an early version of the HGNS were limited to magnetic resonance imaging (MRI) scans of the head, neck, and extremities only. However, patients with the latest model IPGs can now undergo full-body MRI scans. It is important to note that the MRI’s Tesla cannot exceed 1.5T, necessitating specific imaging centers. Other constraints include the inability to adjust device settings remotely, which could mean long travel for minor setting adjustments such as altering start delay or pause times. Furthermore, provider education on operating and managing the device can be time consuming and may also be a barrier to implementation in a clinic. Also challenging may be the availability of an ENT surgery, which plays a critical role in the implantation of the devices and follow-up.

Currently, Inspire Medical Systems is the only FDA-approved hypoglossal nerve stimulation device available in the United States, and globally, more than 45,000 patients have been implanted. However, the field of neurostimulation is rapidly growing. Companies like LivaNova have secured Investigational Device Exemption for their HGNS device. The Genio system by Nyxoah is evaluating the use of bilateral hypoglossal nerve stimulation in patients with OSA and complete concentric collapse of the palate. A multidisciplinary Hypoglossal Nerve Stimulation Clinic is an important component of a comprehensive sleep medicine clinic for patient care and medical education. In the appropriate patient, this emerging technology may provide improvement in OSA severity and symptoms.
 

Dr. Gill is Clinical Associate Professor, Division of Sleep Medicine, Stanford (Calif.) University.

It is estimated that almost one billion people globally are affected by obstructive sleep apnea (OSA) (Benjafield A, et al. Lancet Respir Med. 2019;7[8]:687-98). Despite such high prevalence, the treatment options for OSA are somewhat limited. Continuous positive airway pressure (CPAP), the gold standard therapy, is not viable for many due to difficulties tolerating the device or mask, and thus may not be a realistic long-term solution. As per certain estimates, nearly 50% of CPAP users discontinue treatment by the fifth year (Schoch O, et al. Respiration. 2014;87[2]:121-8). Furthermore, alternative options such as mandibular advancement devices, positional therapy, weight loss, and maxillofacial or palate surgery, also have unique challenges and limitations.

Gill_Kirat_CALIF_web.jpg

First described in 2001, hypoglossal nerve stimulation (HGNS) is a relatively new and emerging technology for the treatment of OSA (Schwartz A, et al. Arch Otolaryngol Head Neck Surg. 2001 Oct;127[10]:1216-23). HGNS therapy was approved by the Food and Drug Administration in 2014 for the treatment of moderate to severe OSA. The therapy involves surgical implantation of the HGNS device, optimization of device settings, and evaluation for treatment response. A physician-led multidisciplinary Hypoglossal Nerve Stimulation Clinic involves collaboration from essential stakeholders, most importantly sleep medicine providers, clinic staff, sleep technologists, and ENT sleep surgeons. Goals of the multidisciplinary program are to ensure timely follow-up, optimization of device settings, and maximizing treatment efficacy. This review describes steps involved in developing a successful multidisciplinary HGNS program within a sleep medicine practice.
 

Patient selection and evaluation

There is growing interest in HGNS relative to conventional CPAP therapy, with many patients presenting to clinic to inquire about this therapy. However, not all patients are candidates for HGNS therapy. Prioritizing appropriate patient selection and education are key first steps. The initial assessments usually occur with a sleep medicine specialist. It begins with confirmation of the diagnosis of OSA in all patients and a concerted effort to troubleshoot and address any barriers to CPAP use before consideration of surgery. Patients who are unwilling to use or unable to tolerate CPAP therapy undergo further evaluation for HGNS therapy. It is important to ensure that patients are also screened for other sleep disorders, such as insomnia or restless leg syndrome, to rule out its contribution to daytime (or nighttime) symptoms.

Other salient inclusion criteria include an apnea-hypopnea index (AHI) between 15-100 events per hour (previously 65), at least 18 years of age, and a body mass index (BMI) less than 40 kg/m² (previously 32). Qualifying patients undergo an updated polysomnography if a recent study is not available. If the polysomnography reveals central and mixed apneas comprising less than 25 percent of the total AHI, patients are referred to ENT Sleep Surgery, and drug-induced sleep endoscopy is offered to examine upper airway anatomy. When a complete concentric collapse of the soft palate is seen on drug-induced sleep endoscopy, surgery is contraindicated. Prior palate surgery or maxillomandibular advancement (MMA) are not contraindications to HGNS therapy.

The patients receive comprehensive information on the nature of the surgery, expected recovery course, and device activation timeline. Perhaps most importantly, the patients receive structured education on HGNS therapy and potential outcomes to set realistic expectations. In the STAR trial, patients experienced a reduction in the AHI of approximately 70% (Strollo P, et al. N Engl J Med. 2014;370[2]:139-49). It is important to note that a response to therapy was defined as a reduction in the AHI by at least 50% and a value less than 20 events/hour (Strollo P, et al. Sleep. 2015;38[10]:1593-8). Therefore, patients who are expecting complete resolution of snoring and/or OSA may not be ideal candidates for surgery. Furthermore, patients who continue to experience fatigue and sleepiness on CPAP despite control of OSA may not experience amelioration of these symptoms with HGNS therapy.
 

Surgery and device management

The surgery, performed under general anesthesia, lasts approximately 3 hours, and may be followed by an overnight hospital stay depending on patient’s comorbidities. The device implantation involves placement of an implantable pulse generator (IPG) in the chest wall and leads to the hypoglossal nerve. The IPG is similar to a pacemaker and functions to stimulate the ipsilateral hypoglossal nerve innervating the tongue during sleep. The most common postoperative complications noted in the STAR trial data include incision site pain and swelling as well as temporary tongue weakness or paresthesia. Postoperative restrictions are minimal and include no heavy lifting for one month after surgery.

One week postsurgery, patients return to the ENT Sleep Surgery Clinic for follow-up, at which time the incisions as well as tongue strength and sensation are evaluated. In a subsequent visit between 4 and 6 weeks postsurgery, patients are evaluated in a joint Sleep Medicine and ENT clinic. They undergo device education and activation of the IPG using a dedicated programmer obtained from the device manufacturer. Device comfort features such as start delay and pause time are also programmed. Furthermore, appropriate tongue movement, lead placement, and voltage range settings are assessed during the visit. The ENT surgery team reevaluates the incision sites and assesses for tongue function and sensation. Patients are instructed to increase the voltage incrementally every week as tolerated with the goal of using the device nightly for the entirety of sleep. If patients tolerate the therapy well during the 2- to 3-month follow-up, a sleep study is scheduled to evaluate treatment effectiveness at the peak tolerable voltage. For those struggling with the therapy, adjustments to electrode configurations should be considered for pulse width, and rate. Occasionally, patients may require awake endoscopy and/or an advanced HGNS titration while asleep to determine the most appropriate settings to optimally control sleep apnea.

Until recently, patients implanted with an early version of the HGNS were limited to magnetic resonance imaging (MRI) scans of the head, neck, and extremities only. However, patients with the latest model IPGs can now undergo full-body MRI scans. It is important to note that the MRI’s Tesla cannot exceed 1.5T, necessitating specific imaging centers. Other constraints include the inability to adjust device settings remotely, which could mean long travel for minor setting adjustments such as altering start delay or pause times. Furthermore, provider education on operating and managing the device can be time consuming and may also be a barrier to implementation in a clinic. Also challenging may be the availability of an ENT surgery, which plays a critical role in the implantation of the devices and follow-up.

Currently, Inspire Medical Systems is the only FDA-approved hypoglossal nerve stimulation device available in the United States, and globally, more than 45,000 patients have been implanted. However, the field of neurostimulation is rapidly growing. Companies like LivaNova have secured Investigational Device Exemption for their HGNS device. The Genio system by Nyxoah is evaluating the use of bilateral hypoglossal nerve stimulation in patients with OSA and complete concentric collapse of the palate. A multidisciplinary Hypoglossal Nerve Stimulation Clinic is an important component of a comprehensive sleep medicine clinic for patient care and medical education. In the appropriate patient, this emerging technology may provide improvement in OSA severity and symptoms.
 

Dr. Gill is Clinical Associate Professor, Division of Sleep Medicine, Stanford (Calif.) University.

It is estimated that almost one billion people globally are affected by obstructive sleep apnea (OSA) (Benjafield A, et al. Lancet Respir Med. 2019;7[8]:687-98). Despite such high prevalence, the treatment options for OSA are somewhat limited. Continuous positive airway pressure (CPAP), the gold standard therapy, is not viable for many due to difficulties tolerating the device or mask, and thus may not be a realistic long-term solution. As per certain estimates, nearly 50% of CPAP users discontinue treatment by the fifth year (Schoch O, et al. Respiration. 2014;87[2]:121-8). Furthermore, alternative options such as mandibular advancement devices, positional therapy, weight loss, and maxillofacial or palate surgery, also have unique challenges and limitations.

Gill_Kirat_CALIF_web.jpg

First described in 2001, hypoglossal nerve stimulation (HGNS) is a relatively new and emerging technology for the treatment of OSA (Schwartz A, et al. Arch Otolaryngol Head Neck Surg. 2001 Oct;127[10]:1216-23). HGNS therapy was approved by the Food and Drug Administration in 2014 for the treatment of moderate to severe OSA. The therapy involves surgical implantation of the HGNS device, optimization of device settings, and evaluation for treatment response. A physician-led multidisciplinary Hypoglossal Nerve Stimulation Clinic involves collaboration from essential stakeholders, most importantly sleep medicine providers, clinic staff, sleep technologists, and ENT sleep surgeons. Goals of the multidisciplinary program are to ensure timely follow-up, optimization of device settings, and maximizing treatment efficacy. This review describes steps involved in developing a successful multidisciplinary HGNS program within a sleep medicine practice.
 

Patient selection and evaluation

There is growing interest in HGNS relative to conventional CPAP therapy, with many patients presenting to clinic to inquire about this therapy. However, not all patients are candidates for HGNS therapy. Prioritizing appropriate patient selection and education are key first steps. The initial assessments usually occur with a sleep medicine specialist. It begins with confirmation of the diagnosis of OSA in all patients and a concerted effort to troubleshoot and address any barriers to CPAP use before consideration of surgery. Patients who are unwilling to use or unable to tolerate CPAP therapy undergo further evaluation for HGNS therapy. It is important to ensure that patients are also screened for other sleep disorders, such as insomnia or restless leg syndrome, to rule out its contribution to daytime (or nighttime) symptoms.

Other salient inclusion criteria include an apnea-hypopnea index (AHI) between 15-100 events per hour (previously 65), at least 18 years of age, and a body mass index (BMI) less than 40 kg/m² (previously 32). Qualifying patients undergo an updated polysomnography if a recent study is not available. If the polysomnography reveals central and mixed apneas comprising less than 25 percent of the total AHI, patients are referred to ENT Sleep Surgery, and drug-induced sleep endoscopy is offered to examine upper airway anatomy. When a complete concentric collapse of the soft palate is seen on drug-induced sleep endoscopy, surgery is contraindicated. Prior palate surgery or maxillomandibular advancement (MMA) are not contraindications to HGNS therapy.

The patients receive comprehensive information on the nature of the surgery, expected recovery course, and device activation timeline. Perhaps most importantly, the patients receive structured education on HGNS therapy and potential outcomes to set realistic expectations. In the STAR trial, patients experienced a reduction in the AHI of approximately 70% (Strollo P, et al. N Engl J Med. 2014;370[2]:139-49). It is important to note that a response to therapy was defined as a reduction in the AHI by at least 50% and a value less than 20 events/hour (Strollo P, et al. Sleep. 2015;38[10]:1593-8). Therefore, patients who are expecting complete resolution of snoring and/or OSA may not be ideal candidates for surgery. Furthermore, patients who continue to experience fatigue and sleepiness on CPAP despite control of OSA may not experience amelioration of these symptoms with HGNS therapy.
 

Surgery and device management

The surgery, performed under general anesthesia, lasts approximately 3 hours, and may be followed by an overnight hospital stay depending on patient’s comorbidities. The device implantation involves placement of an implantable pulse generator (IPG) in the chest wall and leads to the hypoglossal nerve. The IPG is similar to a pacemaker and functions to stimulate the ipsilateral hypoglossal nerve innervating the tongue during sleep. The most common postoperative complications noted in the STAR trial data include incision site pain and swelling as well as temporary tongue weakness or paresthesia. Postoperative restrictions are minimal and include no heavy lifting for one month after surgery.

One week postsurgery, patients return to the ENT Sleep Surgery Clinic for follow-up, at which time the incisions as well as tongue strength and sensation are evaluated. In a subsequent visit between 4 and 6 weeks postsurgery, patients are evaluated in a joint Sleep Medicine and ENT clinic. They undergo device education and activation of the IPG using a dedicated programmer obtained from the device manufacturer. Device comfort features such as start delay and pause time are also programmed. Furthermore, appropriate tongue movement, lead placement, and voltage range settings are assessed during the visit. The ENT surgery team reevaluates the incision sites and assesses for tongue function and sensation. Patients are instructed to increase the voltage incrementally every week as tolerated with the goal of using the device nightly for the entirety of sleep. If patients tolerate the therapy well during the 2- to 3-month follow-up, a sleep study is scheduled to evaluate treatment effectiveness at the peak tolerable voltage. For those struggling with the therapy, adjustments to electrode configurations should be considered for pulse width, and rate. Occasionally, patients may require awake endoscopy and/or an advanced HGNS titration while asleep to determine the most appropriate settings to optimally control sleep apnea.

Until recently, patients implanted with an early version of the HGNS were limited to magnetic resonance imaging (MRI) scans of the head, neck, and extremities only. However, patients with the latest model IPGs can now undergo full-body MRI scans. It is important to note that the MRI’s Tesla cannot exceed 1.5T, necessitating specific imaging centers. Other constraints include the inability to adjust device settings remotely, which could mean long travel for minor setting adjustments such as altering start delay or pause times. Furthermore, provider education on operating and managing the device can be time consuming and may also be a barrier to implementation in a clinic. Also challenging may be the availability of an ENT surgery, which plays a critical role in the implantation of the devices and follow-up.

Currently, Inspire Medical Systems is the only FDA-approved hypoglossal nerve stimulation device available in the United States, and globally, more than 45,000 patients have been implanted. However, the field of neurostimulation is rapidly growing. Companies like LivaNova have secured Investigational Device Exemption for their HGNS device. The Genio system by Nyxoah is evaluating the use of bilateral hypoglossal nerve stimulation in patients with OSA and complete concentric collapse of the palate. A multidisciplinary Hypoglossal Nerve Stimulation Clinic is an important component of a comprehensive sleep medicine clinic for patient care and medical education. In the appropriate patient, this emerging technology may provide improvement in OSA severity and symptoms.
 

Dr. Gill is Clinical Associate Professor, Division of Sleep Medicine, Stanford (Calif.) University.

Obstructive sleep apnea (OSA) affects roughly 1 billion people worldwide, according to a report by the American Academy of Sleep Medicine. Severe OSA has been associated with an elevated risk of all-cause and cardiovascular-specific mortality. Studies support an association between OSA and a host of comorbidities, including hypertension, stroke, atrial fibrillation, mood disorders, and neurocognitive outcomes. Undiagnosed and untreated OSA also has major economic and societal costs, reducing workplace productivity and increasing one’s risk of accidents both on the job and while driving.

Tobias_Lauren_web.jpg

Positive airway pressure (PAP) is widely considered the most effective treatment for OSA. The majority of patients tolerate CPAP: real-world estimates using international big data show good adherence in over 70% of patients. Robust evidence shows that PAP reduces snoring, decreases daytime sleepiness, and improves quality of life in a dose-dependent manner. Economic analyses have also found CPAP to be cost-effective (Streatfeild, et al. Sleep. 2019;42[12]:zsz181).

But what do we know about the impact of PAP on health outcomes? Perhaps the best studied outcome is cardiovascular disease. Results of observational trials have suggested that CPAP adherence was associated with survival (Pepin JL et al. Chest. 2022;161[6]:1657). However, it has been speculated that these findings may have been driven, at least in part, by the “healthy user effect.” This phenomenon refers to the tendency for people who engage in one health-promoting behavior (eg, CPAP adherence) to engage in another as well (eg, eating well, exercising, taking prescribed medications). When we observe that patients who use CPAP live longer, we must ask ourselves whether perhaps their better outcomes resulted from healthy habits in general, as opposed to their CPAP usage per se.

Randomization eliminates the potential for the healthy user effect, by assigning patients to a certain intervention as opposed to simply observing whether they choose to use it. And herein lies one of the great disappointments for our field over the past decade: multiple large-scale randomized controlled trials have failed to demonstrate that CPAP reduces cardiovascular mortality, even in patients with pre-existing CAD. The first two of these were the SAVE (Sleep Apnea Cardiovascular Endpoints) (McEvoy R, et al.  N Engl J Med. 2016;375[10]:919) and RICCADSA (Randomized Intervention with Continuous Positive Airway Pressure in CAD and OSA) (Peker Y, et al. Am J Respir Crit Care Med. 2016;194[5]:613) trials evaluating the effects of PAP on a composite endpoint that included cardiovascular death and nonfatal cardiovascular events. Both trials found no difference between PAP and control groups, leading to a conclusion that PAP did not prevent cardiovascular events in patients with moderate-to-severe OSA and established cardiovascular disease. The ISAAC study (Impact of Sleep Apnea syndrome in the evolution of Acute Coronary syndrome) also failed to show a benefit of CPAP for secondary prevention of cardiovascular events in patients with moderate to severe OSA.

These negative findings were echoed in a recent report by the Agency for Healthcare Research and Quality evaluating a variety of long-term health outcomes in obstructive sleep apnea. The authors stated that “RCTs do not provide evidence that CPAP prescription affects long-term, clinically important outcomes. Specifically, with low strength of evidence, RCTs do not demonstrate that CPAP affects all-cause mortality, various CV outcomes, clinically important changes in psychosocial measures, or other clinical events” (AHRQ, Project ID: SLPT0919, 12/1/2022).

What plausible explanations have been offered for these negative results? Perhaps trials were underpowered. Perhaps patients did not use PAP for a sufficient duration to achieve benefit (usage was under 3 hours in most studies). Perhaps the patients selected for these trials were at such low-risk of adverse outcomes in the first place that treating their OSA didn’t have much impact. Many trials have excluded sleepy patients due to ethical concerns about withholding treatment from this population. But this may have effectively excluded the patients most likely to benefit; in other studies, sleepy patients seem to experience the greatest cardiovascular risk reduction with CPAP. For example, a meta-analysis showed that CPAP is most strongly associated with blood pressure reduction in patients who are sleepy, compared with those with minimally symptomatic OSA (Bratton D, et al. Thorax. 2014;69[12]:1128). And, recent work suggests that even among non-sleepy patients, it might be possible to identify a subset who could benefit from CPAP. A recent analysis suggested that non-sleepy patients who exhibit a higher change in heart rate following a respiratory event may derive greater cardiovascular benefit from CPAP therapy (Azarbarzin, et al. Am J Respir Crit Care Med. 2022;206[6]:767).

Buntak_Vesna_CONN_web.jpg

We are moving toward a more personalized approach to characterizing OSA, which eventually may allow for more nuanced, individualized counseling rather than a “one-size -called-CPAP-fits-all” approach. Until we are there, a patient-centered approach that elicits the presence of sleep-related symptoms and daytime impairment, as opposed to isolated comorbidities, provides the most compelling justification for CPAP.

Obstructive sleep apnea (OSA) affects roughly 1 billion people worldwide, according to a report by the American Academy of Sleep Medicine. Severe OSA has been associated with an elevated risk of all-cause and cardiovascular-specific mortality. Studies support an association between OSA and a host of comorbidities, including hypertension, stroke, atrial fibrillation, mood disorders, and neurocognitive outcomes. Undiagnosed and untreated OSA also has major economic and societal costs, reducing workplace productivity and increasing one’s risk of accidents both on the job and while driving.

Tobias_Lauren_web.jpg

Positive airway pressure (PAP) is widely considered the most effective treatment for OSA. The majority of patients tolerate CPAP: real-world estimates using international big data show good adherence in over 70% of patients. Robust evidence shows that PAP reduces snoring, decreases daytime sleepiness, and improves quality of life in a dose-dependent manner. Economic analyses have also found CPAP to be cost-effective (Streatfeild, et al. Sleep. 2019;42[12]:zsz181).

But what do we know about the impact of PAP on health outcomes? Perhaps the best studied outcome is cardiovascular disease. Results of observational trials have suggested that CPAP adherence was associated with survival (Pepin JL et al. Chest. 2022;161[6]:1657). However, it has been speculated that these findings may have been driven, at least in part, by the “healthy user effect.” This phenomenon refers to the tendency for people who engage in one health-promoting behavior (eg, CPAP adherence) to engage in another as well (eg, eating well, exercising, taking prescribed medications). When we observe that patients who use CPAP live longer, we must ask ourselves whether perhaps their better outcomes resulted from healthy habits in general, as opposed to their CPAP usage per se.

Randomization eliminates the potential for the healthy user effect, by assigning patients to a certain intervention as opposed to simply observing whether they choose to use it. And herein lies one of the great disappointments for our field over the past decade: multiple large-scale randomized controlled trials have failed to demonstrate that CPAP reduces cardiovascular mortality, even in patients with pre-existing CAD. The first two of these were the SAVE (Sleep Apnea Cardiovascular Endpoints) (McEvoy R, et al.  N Engl J Med. 2016;375[10]:919) and RICCADSA (Randomized Intervention with Continuous Positive Airway Pressure in CAD and OSA) (Peker Y, et al. Am J Respir Crit Care Med. 2016;194[5]:613) trials evaluating the effects of PAP on a composite endpoint that included cardiovascular death and nonfatal cardiovascular events. Both trials found no difference between PAP and control groups, leading to a conclusion that PAP did not prevent cardiovascular events in patients with moderate-to-severe OSA and established cardiovascular disease. The ISAAC study (Impact of Sleep Apnea syndrome in the evolution of Acute Coronary syndrome) also failed to show a benefit of CPAP for secondary prevention of cardiovascular events in patients with moderate to severe OSA.

These negative findings were echoed in a recent report by the Agency for Healthcare Research and Quality evaluating a variety of long-term health outcomes in obstructive sleep apnea. The authors stated that “RCTs do not provide evidence that CPAP prescription affects long-term, clinically important outcomes. Specifically, with low strength of evidence, RCTs do not demonstrate that CPAP affects all-cause mortality, various CV outcomes, clinically important changes in psychosocial measures, or other clinical events” (AHRQ, Project ID: SLPT0919, 12/1/2022).

What plausible explanations have been offered for these negative results? Perhaps trials were underpowered. Perhaps patients did not use PAP for a sufficient duration to achieve benefit (usage was under 3 hours in most studies). Perhaps the patients selected for these trials were at such low-risk of adverse outcomes in the first place that treating their OSA didn’t have much impact. Many trials have excluded sleepy patients due to ethical concerns about withholding treatment from this population. But this may have effectively excluded the patients most likely to benefit; in other studies, sleepy patients seem to experience the greatest cardiovascular risk reduction with CPAP. For example, a meta-analysis showed that CPAP is most strongly associated with blood pressure reduction in patients who are sleepy, compared with those with minimally symptomatic OSA (Bratton D, et al. Thorax. 2014;69[12]:1128). And, recent work suggests that even among non-sleepy patients, it might be possible to identify a subset who could benefit from CPAP. A recent analysis suggested that non-sleepy patients who exhibit a higher change in heart rate following a respiratory event may derive greater cardiovascular benefit from CPAP therapy (Azarbarzin, et al. Am J Respir Crit Care Med. 2022;206[6]:767).

Buntak_Vesna_CONN_web.jpg

We are moving toward a more personalized approach to characterizing OSA, which eventually may allow for more nuanced, individualized counseling rather than a “one-size -called-CPAP-fits-all” approach. Until we are there, a patient-centered approach that elicits the presence of sleep-related symptoms and daytime impairment, as opposed to isolated comorbidities, provides the most compelling justification for CPAP.

Obstructive sleep apnea (OSA) affects roughly 1 billion people worldwide, according to a report by the American Academy of Sleep Medicine. Severe OSA has been associated with an elevated risk of all-cause and cardiovascular-specific mortality. Studies support an association between OSA and a host of comorbidities, including hypertension, stroke, atrial fibrillation, mood disorders, and neurocognitive outcomes. Undiagnosed and untreated OSA also has major economic and societal costs, reducing workplace productivity and increasing one’s risk of accidents both on the job and while driving.

Tobias_Lauren_web.jpg

Positive airway pressure (PAP) is widely considered the most effective treatment for OSA. The majority of patients tolerate CPAP: real-world estimates using international big data show good adherence in over 70% of patients. Robust evidence shows that PAP reduces snoring, decreases daytime sleepiness, and improves quality of life in a dose-dependent manner. Economic analyses have also found CPAP to be cost-effective (Streatfeild, et al. Sleep. 2019;42[12]:zsz181).

But what do we know about the impact of PAP on health outcomes? Perhaps the best studied outcome is cardiovascular disease. Results of observational trials have suggested that CPAP adherence was associated with survival (Pepin JL et al. Chest. 2022;161[6]:1657). However, it has been speculated that these findings may have been driven, at least in part, by the “healthy user effect.” This phenomenon refers to the tendency for people who engage in one health-promoting behavior (eg, CPAP adherence) to engage in another as well (eg, eating well, exercising, taking prescribed medications). When we observe that patients who use CPAP live longer, we must ask ourselves whether perhaps their better outcomes resulted from healthy habits in general, as opposed to their CPAP usage per se.

Randomization eliminates the potential for the healthy user effect, by assigning patients to a certain intervention as opposed to simply observing whether they choose to use it. And herein lies one of the great disappointments for our field over the past decade: multiple large-scale randomized controlled trials have failed to demonstrate that CPAP reduces cardiovascular mortality, even in patients with pre-existing CAD. The first two of these were the SAVE (Sleep Apnea Cardiovascular Endpoints) (McEvoy R, et al.  N Engl J Med. 2016;375[10]:919) and RICCADSA (Randomized Intervention with Continuous Positive Airway Pressure in CAD and OSA) (Peker Y, et al. Am J Respir Crit Care Med. 2016;194[5]:613) trials evaluating the effects of PAP on a composite endpoint that included cardiovascular death and nonfatal cardiovascular events. Both trials found no difference between PAP and control groups, leading to a conclusion that PAP did not prevent cardiovascular events in patients with moderate-to-severe OSA and established cardiovascular disease. The ISAAC study (Impact of Sleep Apnea syndrome in the evolution of Acute Coronary syndrome) also failed to show a benefit of CPAP for secondary prevention of cardiovascular events in patients with moderate to severe OSA.

These negative findings were echoed in a recent report by the Agency for Healthcare Research and Quality evaluating a variety of long-term health outcomes in obstructive sleep apnea. The authors stated that “RCTs do not provide evidence that CPAP prescription affects long-term, clinically important outcomes. Specifically, with low strength of evidence, RCTs do not demonstrate that CPAP affects all-cause mortality, various CV outcomes, clinically important changes in psychosocial measures, or other clinical events” (AHRQ, Project ID: SLPT0919, 12/1/2022).

What plausible explanations have been offered for these negative results? Perhaps trials were underpowered. Perhaps patients did not use PAP for a sufficient duration to achieve benefit (usage was under 3 hours in most studies). Perhaps the patients selected for these trials were at such low-risk of adverse outcomes in the first place that treating their OSA didn’t have much impact. Many trials have excluded sleepy patients due to ethical concerns about withholding treatment from this population. But this may have effectively excluded the patients most likely to benefit; in other studies, sleepy patients seem to experience the greatest cardiovascular risk reduction with CPAP. For example, a meta-analysis showed that CPAP is most strongly associated with blood pressure reduction in patients who are sleepy, compared with those with minimally symptomatic OSA (Bratton D, et al. Thorax. 2014;69[12]:1128). And, recent work suggests that even among non-sleepy patients, it might be possible to identify a subset who could benefit from CPAP. A recent analysis suggested that non-sleepy patients who exhibit a higher change in heart rate following a respiratory event may derive greater cardiovascular benefit from CPAP therapy (Azarbarzin, et al. Am J Respir Crit Care Med. 2022;206[6]:767).

Buntak_Vesna_CONN_web.jpg

We are moving toward a more personalized approach to characterizing OSA, which eventually may allow for more nuanced, individualized counseling rather than a “one-size -called-CPAP-fits-all” approach. Until we are there, a patient-centered approach that elicits the presence of sleep-related symptoms and daytime impairment, as opposed to isolated comorbidities, provides the most compelling justification for CPAP.

“Artificial intelligence (AI) in healthcare refers to the use of machine learning (ML), deep learning, natural language processing, and computer vision to process and analyze large amounts of health care data.”

The preceding line is a direct quote from ChatGPT when prompted with the question “What is AI in health care?” (OpenAI, 2022). AI has rapidly infiltrated our lives. From using facial recognition software to unlock our cellphones to scrolling through targeted media suggested by streaming services, our daily existence is interwoven with algorithms. With the recent introduction of GPT-3 (the model that powers ChatGPT) in late 2022 and its even more capable successor, GPT-4, in March 2023, AI will continue to dominate our everyday environment in even more complex and meaningful ways.

Tan_Miranda_CALIF_web.jpg

For sleep medicine, the initial applications of AI in this field have been innovative and promising. To date, AI has been leveraged to explore sleep staging, respiratory event scoring, characterization of insomnia, prediction of circadian timing from gene expression, endotyping, and phenotyping of obstructive sleep apnea (OSA) (Bandyopadhyay A, et al. Sleep Breath. 2023;27[1]:39). Pépin and colleagues (JAMA Netw Open. 2020;3[1]:e1919657) combined ML with mandibular movement to diagnose OSA with a reasonable agreement to polysomnography as a novel home-based alternative for diagnosis. AI has also been used to predict adherence to positive airway pressure (PAP) therapy in OSA (Scioscia G, et al. Inform Health Soc Care. 2022;47[3]:274) and as a digital intervention tool accessed via a smartphone app for people with insomnia (Philip P, et al, J Med Internet Res. 2020;22[12]:e24268). The data-rich field of sleep medicine is primed for further advancements through AI, albeit with a few hurdles and regulations to overcome before becoming mainstream.
 

Future promise

Sleep medicine is uniquely positioned to develop robust AI algorithms because of its vast data trove. Using AI, scientists can efficiently analyze the raw data from polysomnography, consumer sleep technology (CST), and nightly remote monitoring (from PAP devices) to substantially improve comprehension and management of sleep disorders.

AI can redefine OSA through analysis of the big data available, rather than solely relying on the apnea-hypopnea index. In addition, novel variables such as facial structure; snoring index; temperature trends; and sleep environment, position, and timing using a camera-based contactless technology may be incorporated to enhance the diagnostic accuracy for OSA or better describe sleep quality. AI algorithms can also be embedded into the electronic health record (EHR) to facilitate screening for sleep disorders using patient characteristics, thus accelerating the recognition and evaluation of possible sleep disorders.

Bhargava_Sumit_CALIF_web.jpg

New ways of collecting data may deliver deeper insights into sleep health, as well. CST such as wearables, nearables, and phone applications are improving with each iteration, resulting in more data about sleep for millions of people over thousands of nights.

AI can help achieve precision medicine by integrating multimodal data to establish endotypes and phenotypes of various sleep disorders. Delineating endotypes and phenotypes allows for personalized treatment recommendations, which may improve patient adherence and health outcomes.

Treatment personalization can also be achieved through AI by predicting compliance to various therapies and responses, as well as by discovering alternative forms of delivery to accomplish desired health outcomes. For example, to predict PAP compliance, we can record a patient encounter and use natural language processing to analyze their opinion of their treatment, extracting relevant keywords and combining such processing with other available data, such as environmental factors, sleep schedule, medical history, and other information extracted from the EHR. As another example, AI can determine the optimal time for cancer therapy by predicting a patient’s circadian timing (Hesse J, et al. Cancers (Basel). 2020;12[11]:3103). Circadian timing of drug delivery may be relevant in other specialties including cardiovascular disease, endocrine disorders, and psychiatric conditions due to its associations with sleep. Integration of the various “-omics” (eg, proteomics, genomics, and transcriptomics) with physiologic, behavioral, and environmental data can offer opportunities for drug discovery and possible prediction of sleep disorders and sleep-related morbidity. Although generative pretrained transformers are currently used to predict text (ie, ChatGPT), it is theoretically possible to also apply this technique to identify patients at risk for future sleep disorders from an earlier age.
 

Challenges to an AI renaissance

Despite making strides in numerous specialties such as radiology, ophthalmology, pathology, oncology, and dermatology, AI has not yet gained mainstream usage. Why isn’t AI as ubiquitous and heavily entrenched in health care as it is in other industries? According to the National Academy of Medicine’s AI in Healthcare: The Hope, The Hype, The Promise, The Peril, there are several realities to address before we fully embrace the AI revolution (Matheny M, et al. 2019).

First, AI algorithms should be trained on quality data that are representative of the population. Interoperability between health care systems and standardization across platforms is required to access large volumes of quality data. The current framework for data gathering is limited due to regulations, patient privacy concerns, and organizational preferences. The challenges to data acquisition and standardization of information will continue to snarl progress unless there are legislative remedies.

Furthermore, datasets should be diverse enough to avoid introducing bias into the AI algorithm. If the dataset is limited and health inequities (eg, societal bias and social determinants of health) are excluded from the training set, then the outcome will perpetuate further explicit and implicit biases.

The Food and Drug Administration (FDA) reviews and authorizes AI/ML-enabled devices. Its current regulatory structure treats AI as a static process and does not allow for exercise of its intrinsic ability to continuously learn from additional data, thereby preventing it from becoming more accurate and evolving with the population over time. A more flexible approach is needed.

Lastly, recent advanced AI algorithms including deep learning and neural network methodology function like a “black box.” The models are not explainable or transparent. Without clear comprehension of its methods, acceptance in clinical practice will be guarded and further risk of inherent biases may ensue.
 

A path forward

But these challenges, like any, can be overcome. Research in the area of differential privacy and the adoption of recent data-sharing standards (eg, HL7 FHIR) can facilitate access to training data (Saripalle R, et al. J Biomed Inform. 2019;94:103188). Regulators are also open to incorporating feedback from the AI research community and industry in favor of innovation in this frenetic domain. The FDA developed the AI/ML Software as a Medical Device Action Plan in response to stakeholder feedback for oversight (FDA, 2021). Specifically, the “Good Machine Learning Practice” will be developed to describe AI/ML best practices (eg, data management, training, interpretability, evaluation, and documentation) to guide product development and standardization.

Sleep medicine has significantly progressed over the last several decades. Rather than maintain the status quo, AI can help fill the existing knowledge gaps, augment clinical practice, and streamline operations by analyzing and processing data at a volume and efficiency beyond human capacity. Fallibility is inevitable in machines and humans; however, like humans, machines can improve with continued training and exposure.

We asked ChatGPT about the future of AI in sleep medicine. It states that AI could have a “significant impact” on sleep disorders diagnosis, treatment, prevention, and sleep tracking and monitoring. Only time will tell if its claims are accurate.

Dr. Tan is Clinical Associate Professor with the Division of Sleep Medicine at the Stanford University School of Medicine. Dr. Bhargava is Clinical Professor with the Division of Pediatric Pulmonary, Asthma, and Sleep Medicine at the Stanford University School of Medicine.

“Artificial intelligence (AI) in healthcare refers to the use of machine learning (ML), deep learning, natural language processing, and computer vision to process and analyze large amounts of health care data.”

The preceding line is a direct quote from ChatGPT when prompted with the question “What is AI in health care?” (OpenAI, 2022). AI has rapidly infiltrated our lives. From using facial recognition software to unlock our cellphones to scrolling through targeted media suggested by streaming services, our daily existence is interwoven with algorithms. With the recent introduction of GPT-3 (the model that powers ChatGPT) in late 2022 and its even more capable successor, GPT-4, in March 2023, AI will continue to dominate our everyday environment in even more complex and meaningful ways.

Tan_Miranda_CALIF_web.jpg

For sleep medicine, the initial applications of AI in this field have been innovative and promising. To date, AI has been leveraged to explore sleep staging, respiratory event scoring, characterization of insomnia, prediction of circadian timing from gene expression, endotyping, and phenotyping of obstructive sleep apnea (OSA) (Bandyopadhyay A, et al. Sleep Breath. 2023;27[1]:39). Pépin and colleagues (JAMA Netw Open. 2020;3[1]:e1919657) combined ML with mandibular movement to diagnose OSA with a reasonable agreement to polysomnography as a novel home-based alternative for diagnosis. AI has also been used to predict adherence to positive airway pressure (PAP) therapy in OSA (Scioscia G, et al. Inform Health Soc Care. 2022;47[3]:274) and as a digital intervention tool accessed via a smartphone app for people with insomnia (Philip P, et al, J Med Internet Res. 2020;22[12]:e24268). The data-rich field of sleep medicine is primed for further advancements through AI, albeit with a few hurdles and regulations to overcome before becoming mainstream.
 

Future promise

Sleep medicine is uniquely positioned to develop robust AI algorithms because of its vast data trove. Using AI, scientists can efficiently analyze the raw data from polysomnography, consumer sleep technology (CST), and nightly remote monitoring (from PAP devices) to substantially improve comprehension and management of sleep disorders.

AI can redefine OSA through analysis of the big data available, rather than solely relying on the apnea-hypopnea index. In addition, novel variables such as facial structure; snoring index; temperature trends; and sleep environment, position, and timing using a camera-based contactless technology may be incorporated to enhance the diagnostic accuracy for OSA or better describe sleep quality. AI algorithms can also be embedded into the electronic health record (EHR) to facilitate screening for sleep disorders using patient characteristics, thus accelerating the recognition and evaluation of possible sleep disorders.

Bhargava_Sumit_CALIF_web.jpg

New ways of collecting data may deliver deeper insights into sleep health, as well. CST such as wearables, nearables, and phone applications are improving with each iteration, resulting in more data about sleep for millions of people over thousands of nights.

AI can help achieve precision medicine by integrating multimodal data to establish endotypes and phenotypes of various sleep disorders. Delineating endotypes and phenotypes allows for personalized treatment recommendations, which may improve patient adherence and health outcomes.

Treatment personalization can also be achieved through AI by predicting compliance to various therapies and responses, as well as by discovering alternative forms of delivery to accomplish desired health outcomes. For example, to predict PAP compliance, we can record a patient encounter and use natural language processing to analyze their opinion of their treatment, extracting relevant keywords and combining such processing with other available data, such as environmental factors, sleep schedule, medical history, and other information extracted from the EHR. As another example, AI can determine the optimal time for cancer therapy by predicting a patient’s circadian timing (Hesse J, et al. Cancers (Basel). 2020;12[11]:3103). Circadian timing of drug delivery may be relevant in other specialties including cardiovascular disease, endocrine disorders, and psychiatric conditions due to its associations with sleep. Integration of the various “-omics” (eg, proteomics, genomics, and transcriptomics) with physiologic, behavioral, and environmental data can offer opportunities for drug discovery and possible prediction of sleep disorders and sleep-related morbidity. Although generative pretrained transformers are currently used to predict text (ie, ChatGPT), it is theoretically possible to also apply this technique to identify patients at risk for future sleep disorders from an earlier age.
 

Challenges to an AI renaissance

Despite making strides in numerous specialties such as radiology, ophthalmology, pathology, oncology, and dermatology, AI has not yet gained mainstream usage. Why isn’t AI as ubiquitous and heavily entrenched in health care as it is in other industries? According to the National Academy of Medicine’s AI in Healthcare: The Hope, The Hype, The Promise, The Peril, there are several realities to address before we fully embrace the AI revolution (Matheny M, et al. 2019).

First, AI algorithms should be trained on quality data that are representative of the population. Interoperability between health care systems and standardization across platforms is required to access large volumes of quality data. The current framework for data gathering is limited due to regulations, patient privacy concerns, and organizational preferences. The challenges to data acquisition and standardization of information will continue to snarl progress unless there are legislative remedies.

Furthermore, datasets should be diverse enough to avoid introducing bias into the AI algorithm. If the dataset is limited and health inequities (eg, societal bias and social determinants of health) are excluded from the training set, then the outcome will perpetuate further explicit and implicit biases.

The Food and Drug Administration (FDA) reviews and authorizes AI/ML-enabled devices. Its current regulatory structure treats AI as a static process and does not allow for exercise of its intrinsic ability to continuously learn from additional data, thereby preventing it from becoming more accurate and evolving with the population over time. A more flexible approach is needed.

Lastly, recent advanced AI algorithms including deep learning and neural network methodology function like a “black box.” The models are not explainable or transparent. Without clear comprehension of its methods, acceptance in clinical practice will be guarded and further risk of inherent biases may ensue.
 

A path forward

But these challenges, like any, can be overcome. Research in the area of differential privacy and the adoption of recent data-sharing standards (eg, HL7 FHIR) can facilitate access to training data (Saripalle R, et al. J Biomed Inform. 2019;94:103188). Regulators are also open to incorporating feedback from the AI research community and industry in favor of innovation in this frenetic domain. The FDA developed the AI/ML Software as a Medical Device Action Plan in response to stakeholder feedback for oversight (FDA, 2021). Specifically, the “Good Machine Learning Practice” will be developed to describe AI/ML best practices (eg, data management, training, interpretability, evaluation, and documentation) to guide product development and standardization.

Sleep medicine has significantly progressed over the last several decades. Rather than maintain the status quo, AI can help fill the existing knowledge gaps, augment clinical practice, and streamline operations by analyzing and processing data at a volume and efficiency beyond human capacity. Fallibility is inevitable in machines and humans; however, like humans, machines can improve with continued training and exposure.

We asked ChatGPT about the future of AI in sleep medicine. It states that AI could have a “significant impact” on sleep disorders diagnosis, treatment, prevention, and sleep tracking and monitoring. Only time will tell if its claims are accurate.

Dr. Tan is Clinical Associate Professor with the Division of Sleep Medicine at the Stanford University School of Medicine. Dr. Bhargava is Clinical Professor with the Division of Pediatric Pulmonary, Asthma, and Sleep Medicine at the Stanford University School of Medicine.

“Artificial intelligence (AI) in healthcare refers to the use of machine learning (ML), deep learning, natural language processing, and computer vision to process and analyze large amounts of health care data.”

The preceding line is a direct quote from ChatGPT when prompted with the question “What is AI in health care?” (OpenAI, 2022). AI has rapidly infiltrated our lives. From using facial recognition software to unlock our cellphones to scrolling through targeted media suggested by streaming services, our daily existence is interwoven with algorithms. With the recent introduction of GPT-3 (the model that powers ChatGPT) in late 2022 and its even more capable successor, GPT-4, in March 2023, AI will continue to dominate our everyday environment in even more complex and meaningful ways.

Tan_Miranda_CALIF_web.jpg

For sleep medicine, the initial applications of AI in this field have been innovative and promising. To date, AI has been leveraged to explore sleep staging, respiratory event scoring, characterization of insomnia, prediction of circadian timing from gene expression, endotyping, and phenotyping of obstructive sleep apnea (OSA) (Bandyopadhyay A, et al. Sleep Breath. 2023;27[1]:39). Pépin and colleagues (JAMA Netw Open. 2020;3[1]:e1919657) combined ML with mandibular movement to diagnose OSA with a reasonable agreement to polysomnography as a novel home-based alternative for diagnosis. AI has also been used to predict adherence to positive airway pressure (PAP) therapy in OSA (Scioscia G, et al. Inform Health Soc Care. 2022;47[3]:274) and as a digital intervention tool accessed via a smartphone app for people with insomnia (Philip P, et al, J Med Internet Res. 2020;22[12]:e24268). The data-rich field of sleep medicine is primed for further advancements through AI, albeit with a few hurdles and regulations to overcome before becoming mainstream.
 

Future promise

Sleep medicine is uniquely positioned to develop robust AI algorithms because of its vast data trove. Using AI, scientists can efficiently analyze the raw data from polysomnography, consumer sleep technology (CST), and nightly remote monitoring (from PAP devices) to substantially improve comprehension and management of sleep disorders.

AI can redefine OSA through analysis of the big data available, rather than solely relying on the apnea-hypopnea index. In addition, novel variables such as facial structure; snoring index; temperature trends; and sleep environment, position, and timing using a camera-based contactless technology may be incorporated to enhance the diagnostic accuracy for OSA or better describe sleep quality. AI algorithms can also be embedded into the electronic health record (EHR) to facilitate screening for sleep disorders using patient characteristics, thus accelerating the recognition and evaluation of possible sleep disorders.

Bhargava_Sumit_CALIF_web.jpg

New ways of collecting data may deliver deeper insights into sleep health, as well. CST such as wearables, nearables, and phone applications are improving with each iteration, resulting in more data about sleep for millions of people over thousands of nights.

AI can help achieve precision medicine by integrating multimodal data to establish endotypes and phenotypes of various sleep disorders. Delineating endotypes and phenotypes allows for personalized treatment recommendations, which may improve patient adherence and health outcomes.

Treatment personalization can also be achieved through AI by predicting compliance to various therapies and responses, as well as by discovering alternative forms of delivery to accomplish desired health outcomes. For example, to predict PAP compliance, we can record a patient encounter and use natural language processing to analyze their opinion of their treatment, extracting relevant keywords and combining such processing with other available data, such as environmental factors, sleep schedule, medical history, and other information extracted from the EHR. As another example, AI can determine the optimal time for cancer therapy by predicting a patient’s circadian timing (Hesse J, et al. Cancers (Basel). 2020;12[11]:3103). Circadian timing of drug delivery may be relevant in other specialties including cardiovascular disease, endocrine disorders, and psychiatric conditions due to its associations with sleep. Integration of the various “-omics” (eg, proteomics, genomics, and transcriptomics) with physiologic, behavioral, and environmental data can offer opportunities for drug discovery and possible prediction of sleep disorders and sleep-related morbidity. Although generative pretrained transformers are currently used to predict text (ie, ChatGPT), it is theoretically possible to also apply this technique to identify patients at risk for future sleep disorders from an earlier age.
 

Challenges to an AI renaissance

Despite making strides in numerous specialties such as radiology, ophthalmology, pathology, oncology, and dermatology, AI has not yet gained mainstream usage. Why isn’t AI as ubiquitous and heavily entrenched in health care as it is in other industries? According to the National Academy of Medicine’s AI in Healthcare: The Hope, The Hype, The Promise, The Peril, there are several realities to address before we fully embrace the AI revolution (Matheny M, et al. 2019).

First, AI algorithms should be trained on quality data that are representative of the population. Interoperability between health care systems and standardization across platforms is required to access large volumes of quality data. The current framework for data gathering is limited due to regulations, patient privacy concerns, and organizational preferences. The challenges to data acquisition and standardization of information will continue to snarl progress unless there are legislative remedies.

Furthermore, datasets should be diverse enough to avoid introducing bias into the AI algorithm. If the dataset is limited and health inequities (eg, societal bias and social determinants of health) are excluded from the training set, then the outcome will perpetuate further explicit and implicit biases.

The Food and Drug Administration (FDA) reviews and authorizes AI/ML-enabled devices. Its current regulatory structure treats AI as a static process and does not allow for exercise of its intrinsic ability to continuously learn from additional data, thereby preventing it from becoming more accurate and evolving with the population over time. A more flexible approach is needed.

Lastly, recent advanced AI algorithms including deep learning and neural network methodology function like a “black box.” The models are not explainable or transparent. Without clear comprehension of its methods, acceptance in clinical practice will be guarded and further risk of inherent biases may ensue.
 

A path forward

But these challenges, like any, can be overcome. Research in the area of differential privacy and the adoption of recent data-sharing standards (eg, HL7 FHIR) can facilitate access to training data (Saripalle R, et al. J Biomed Inform. 2019;94:103188). Regulators are also open to incorporating feedback from the AI research community and industry in favor of innovation in this frenetic domain. The FDA developed the AI/ML Software as a Medical Device Action Plan in response to stakeholder feedback for oversight (FDA, 2021). Specifically, the “Good Machine Learning Practice” will be developed to describe AI/ML best practices (eg, data management, training, interpretability, evaluation, and documentation) to guide product development and standardization.

Sleep medicine has significantly progressed over the last several decades. Rather than maintain the status quo, AI can help fill the existing knowledge gaps, augment clinical practice, and streamline operations by analyzing and processing data at a volume and efficiency beyond human capacity. Fallibility is inevitable in machines and humans; however, like humans, machines can improve with continued training and exposure.

We asked ChatGPT about the future of AI in sleep medicine. It states that AI could have a “significant impact” on sleep disorders diagnosis, treatment, prevention, and sleep tracking and monitoring. Only time will tell if its claims are accurate.

Dr. Tan is Clinical Associate Professor with the Division of Sleep Medicine at the Stanford University School of Medicine. Dr. Bhargava is Clinical Professor with the Division of Pediatric Pulmonary, Asthma, and Sleep Medicine at the Stanford University School of Medicine.

In our current society, it is likely that the “skinny patient with COPD” who walks into your clinic is less and less your “traditional” patient with COPD. We are seeing in our health care systems more of the “blue bloaters” – patients with COPD and significant obesity. This phenotype is representing what we are seeing worldwide as a consequence of the rising obesity prevalence. In the United States, the prepandemic (2017-2020) estimated percentage of adults over the age of 40 with obesity, defined as a body mass index (BMI) of at least 30 kg/m², was over 40%. Moreover, the estimated percentage of adults with morbid obesity (BMI at least 40 kg/m₂) is close to 10% (Akinbami, LJ et al. Vital Health Stat. 2022:190:1-36) and trending up. These patients with the “triple overlap” of morbid obesity, COPD, and awake daytime hypercapnia are being seen in clinics and in-hospital settings with increasing frequency, often presenting with complicating comorbidities such as acute respiratory failure, acute heart failure, kidney disease, or pulmonary hypertension. We are now faced with managing these patients with complex disease.

The obesity paradox does not seem applicable in the triple overlap phenotype. Patients with COPD who are overweight, defined as “mild obesity,” have lower mortality when compared with normal weight and underweight patients with COPD; however, this effect diminishes when BMI increases beyond 32 kg/m². With increasing obesity severity and aging, the risk of both obstructive sleep apnea (OSA) and hypoventilation increases. It is well documented that COPD-OSA overlap is linked to worse outcomes and that continuous positive airway pressure (CPAP) as first-line therapy decreases readmission rates and mortality. The triple overlap phenotypic patients, however, are presenting with chronic hypercapnic respiratory failure in a backdrop of morbid obesity, unlike the stable COPD-OSA overlap. The pathophysiology of hypoventilation in obesity is complex and multifactorial, and, although significant overlaps likely exist with comorbid COPD, by current definitions, to establish a diagnosis of obesity hypoventilation syndrome (OHS), one must have excluded other causes of hypoventilation, such as COPD.

162136_graphic_web.png

These patients with the triple overlap of morbid obesity, awake daytime hypercapnia, and COPD are the subset of patients that providers struggle to fit in a diagnosis or in clinical research trials.
 

The triple overlap is a distinct syndrome

Different labels have been used in the medical literature: hypercapnic OSA-COPD overlap, morbid obesity and OSA-COPD overlap, hypercapnic morbidly obese COPD and OHS-COPD overlap. A better characterization of this distinctive phenotype is much needed. Patients with OSA-COPD overlap, for example, have an increased propensity to develop hypercapnia at higher FEV₁ when compared with COPD without OSA – but this is thought to be a consequence of prolonged and frequent apneas and hypopneas compounded with obesity-related central hypoventilation. We found that morbidly obese patients with OSA-COPD overlap have a higher hypoxia burden, more severe OSA, and are frequently prescribed noninvasive ventilation after a failed titration polysomnogram (Htun ZM, et al. Am J Respir Crit Care Med. 2019;199:A1382), perhaps signaling a distinctive phenotype with worse outcomes, but the study had the inherent limitations of a single-center, retrospective design lacking data on awake hypercapnia. On the other side, the term OHS-COPD is contradictory and confusing based on current OHS diagnostic criteria.

In standardizing diagnostic criteria for patients with this triple overlap syndrome, challenges remain: would the patient with a BMI of 70 kg/m² and fixed chronic airflow obstruction with FEV₁ 72% fall under the category of hypercapnic COPD vs OHS? Do these patients have worse outcomes regardless of their predominant feature? Would outcomes change if the apnea hypopnea index (AHI) is 10/h vs 65/h? More importantly, do patients with the triple overlap of COPD, morbid obesity, and daytime hypercapnia have worse outcomes when compared with hypercapnic COPD, or OHS with/without OSA? These questions can be better addressed once we agree on a definition. The patients with triple overlap syndrome have been traditionally excluded from clinical trials: the patient with morbid obesity has been excluded from chronic hypercapnic COPD clinical trials, and the patient with COPD has been excluded from OHS trials.

There are no specific clinical guidelines for this triple overlap phenotype. Positive airway pressure is the mainstay of treatment. CPAP is recommended as first-line therapy for patients with OSA-COPD overlap syndrome, while noninvasive ventilation (NIV) with bilevel positive airway pressure (BPAP) is recommended as first-line for the stable ambulatory hypercapnic patient with COPD. It is unclear if NIV is superior to CPAP in patients with triple overlap syndrome, although recently published data showed greater efficacy in reducing carbon dioxide (PaCO₂) and improving quality of life in a small group of subjects (Zheng et al. J Clin Sleep Med. 2022;18[1]:99-107). To take a step further, the subtleties of NIV set up, such as rise time and minimum inspiratory time, are contradictory: the goal in ventilating patients with COPD is to shorten inspiratory time, prolonging expiratory time, therefore allowing a shortened inspiratory cycle. In obesity, ventilation strategies aim to prolong and sustain inspiratory time to improve ventilation and dependent atelectasis. Another area of uncertainty is device selection. Should we aim to provide a respiratory assist device (RAD): the traditional, rent to own bilevel PAP without auto-expiratory positive airway pressure (EPAP) capabilities and lower maximum inspiratory pressure delivery capacity, vs a home mechanical ventilator at a higher expense, life-time rental, and one-way only data monitoring, which limits remote prescription adjustments, but allow auto-EPAP settings for patients with comorbid OSA? More importantly, how do we get these patients, who do not fit in any of the specified insurance criteria for PAP therapy approved for treatment?

A uniform diagnostic definition and clear taxonomy allows for resource allocation, from government funded grants for clinical trials to a better-informed distribution of health care systems resources and support health care policy changes to improve patient-centric outcomes. Here, we propose that the morbidly obese patient (BMI >40 kg/m2) with chronic airflow obstruction and a forced expiratory ratio (FEV₁/FVC) <0.7 with awake daytime hypercapnia (PaCO₂ > 45 mm Hg) represents a different entity/phenotype and fits best under the triple overlap syndrome taxonomy.

We suspect that these patients have worse outcomes, including comorbidity burden, quality of life, exacerbation rates, longer hospital length-of-stay, and respiratory and all-cause mortality. Large, multicenter, controlled trials comparing the long-term effectiveness of NIV and CPAP: measurements of respiratory function, gas exchange, blood pressure, and health related quality of life are needed. This is a group of patients that may specifically benefit from volume-targeted pressure support mode ventilation with auto-EPAP capabilities upon discharge from the hospital after an acute exacerbation.
 

Inpatient (sleep medicine) and outpatient transitions

In patients hospitalized with the triple overlap syndrome, there are certain considerations that are of special interest. Given comorbid hypercapnia and limited data on NIV superiority over CPAP, a sleep study should not be needed for NIV qualification. In addition, the medical team may consider the following (Figure 1):

162136_fig1_web.jpg

1. Noninvasive Ventilation:

a. Maintaining a high-pressure support differential between inspiratory positive airway pressure (IPAP) and EPAP. This can usually be achieved at 8-10 cm H₂O, further adjusting to target a tidal volume (Vt) of 8 mL/kg of ideal body weight (IBW).

b. Higher EPAP: To overcome dependent atelectasis, improve ventilation-perfusion (VQ) matching, and better treat upper airway resistance both during wakefulness and sleep. Also, adjustments of EPAP at bedside should be considered to counteract auto-PEEP-related ineffective triggering if observed.

c. OSA screening and EPAP adjustment: for high residual obstructive apneas or hypopneas if data are available on the NIV device, or with the use of peripheral arterial tonometry sleep testing devices with NIV on overnight before discharge.

d. Does the patient meet criteria for oxygen supplementation at home? Wean oxygen off, if possible.

2. Case-managers can help establish services with a durable medical equipment provider with expertise in advanced PAP devices.3. Obesity management, Consider referral to an obesity management program for lifestyle/dietary modifications along with pharmacotherapy or bariatric surgery interventions.

4. Close follow-up, track exacerbations. Device download data are crucial to monitor adherence/tolerance and treatment effectiveness with particular interest in AHI, oximetry, and CO₂ trends monitoring. Some patients may need dedicated titration polysomnograms to adjust ventilation settings, for optimization of residual OSA or for oxygen addition or discontinuation.
 

Conclusion

Patients with the triple overlap phenotype have not been systematically defined, studied, or included in clinical trials. We anticipate that these patients have worse outcomes: quality of life, symptom and comorbidity burden, exacerbation rates, in-hospital mortality, longer hospital stay and ICU stay, and respiratory and all-cause mortality. This is a group of patients that may specifically benefit from domiciliary NIV set-up upon discharge from the hospital with close follow-up. Properly identifying these patients will help pulmonologists and health care systems direct resources to optimally manage this complex group of patients. Funding of research trials to support clinical guidelines development should be prioritized. Triple overlap syndrome is different from COPD-OSA overlap, OHS with moderate to severe OSA, or OHS without significant OSA.

In our current society, it is likely that the “skinny patient with COPD” who walks into your clinic is less and less your “traditional” patient with COPD. We are seeing in our health care systems more of the “blue bloaters” – patients with COPD and significant obesity. This phenotype is representing what we are seeing worldwide as a consequence of the rising obesity prevalence. In the United States, the prepandemic (2017-2020) estimated percentage of adults over the age of 40 with obesity, defined as a body mass index (BMI) of at least 30 kg/m², was over 40%. Moreover, the estimated percentage of adults with morbid obesity (BMI at least 40 kg/m₂) is close to 10% (Akinbami, LJ et al. Vital Health Stat. 2022:190:1-36) and trending up. These patients with the “triple overlap” of morbid obesity, COPD, and awake daytime hypercapnia are being seen in clinics and in-hospital settings with increasing frequency, often presenting with complicating comorbidities such as acute respiratory failure, acute heart failure, kidney disease, or pulmonary hypertension. We are now faced with managing these patients with complex disease.

The obesity paradox does not seem applicable in the triple overlap phenotype. Patients with COPD who are overweight, defined as “mild obesity,” have lower mortality when compared with normal weight and underweight patients with COPD; however, this effect diminishes when BMI increases beyond 32 kg/m². With increasing obesity severity and aging, the risk of both obstructive sleep apnea (OSA) and hypoventilation increases. It is well documented that COPD-OSA overlap is linked to worse outcomes and that continuous positive airway pressure (CPAP) as first-line therapy decreases readmission rates and mortality. The triple overlap phenotypic patients, however, are presenting with chronic hypercapnic respiratory failure in a backdrop of morbid obesity, unlike the stable COPD-OSA overlap. The pathophysiology of hypoventilation in obesity is complex and multifactorial, and, although significant overlaps likely exist with comorbid COPD, by current definitions, to establish a diagnosis of obesity hypoventilation syndrome (OHS), one must have excluded other causes of hypoventilation, such as COPD.

162136_graphic_web.png

These patients with the triple overlap of morbid obesity, awake daytime hypercapnia, and COPD are the subset of patients that providers struggle to fit in a diagnosis or in clinical research trials.
 

The triple overlap is a distinct syndrome

Different labels have been used in the medical literature: hypercapnic OSA-COPD overlap, morbid obesity and OSA-COPD overlap, hypercapnic morbidly obese COPD and OHS-COPD overlap. A better characterization of this distinctive phenotype is much needed. Patients with OSA-COPD overlap, for example, have an increased propensity to develop hypercapnia at higher FEV₁ when compared with COPD without OSA – but this is thought to be a consequence of prolonged and frequent apneas and hypopneas compounded with obesity-related central hypoventilation. We found that morbidly obese patients with OSA-COPD overlap have a higher hypoxia burden, more severe OSA, and are frequently prescribed noninvasive ventilation after a failed titration polysomnogram (Htun ZM, et al. Am J Respir Crit Care Med. 2019;199:A1382), perhaps signaling a distinctive phenotype with worse outcomes, but the study had the inherent limitations of a single-center, retrospective design lacking data on awake hypercapnia. On the other side, the term OHS-COPD is contradictory and confusing based on current OHS diagnostic criteria.

In standardizing diagnostic criteria for patients with this triple overlap syndrome, challenges remain: would the patient with a BMI of 70 kg/m² and fixed chronic airflow obstruction with FEV₁ 72% fall under the category of hypercapnic COPD vs OHS? Do these patients have worse outcomes regardless of their predominant feature? Would outcomes change if the apnea hypopnea index (AHI) is 10/h vs 65/h? More importantly, do patients with the triple overlap of COPD, morbid obesity, and daytime hypercapnia have worse outcomes when compared with hypercapnic COPD, or OHS with/without OSA? These questions can be better addressed once we agree on a definition. The patients with triple overlap syndrome have been traditionally excluded from clinical trials: the patient with morbid obesity has been excluded from chronic hypercapnic COPD clinical trials, and the patient with COPD has been excluded from OHS trials.

There are no specific clinical guidelines for this triple overlap phenotype. Positive airway pressure is the mainstay of treatment. CPAP is recommended as first-line therapy for patients with OSA-COPD overlap syndrome, while noninvasive ventilation (NIV) with bilevel positive airway pressure (BPAP) is recommended as first-line for the stable ambulatory hypercapnic patient with COPD. It is unclear if NIV is superior to CPAP in patients with triple overlap syndrome, although recently published data showed greater efficacy in reducing carbon dioxide (PaCO₂) and improving quality of life in a small group of subjects (Zheng et al. J Clin Sleep Med. 2022;18[1]:99-107). To take a step further, the subtleties of NIV set up, such as rise time and minimum inspiratory time, are contradictory: the goal in ventilating patients with COPD is to shorten inspiratory time, prolonging expiratory time, therefore allowing a shortened inspiratory cycle. In obesity, ventilation strategies aim to prolong and sustain inspiratory time to improve ventilation and dependent atelectasis. Another area of uncertainty is device selection. Should we aim to provide a respiratory assist device (RAD): the traditional, rent to own bilevel PAP without auto-expiratory positive airway pressure (EPAP) capabilities and lower maximum inspiratory pressure delivery capacity, vs a home mechanical ventilator at a higher expense, life-time rental, and one-way only data monitoring, which limits remote prescription adjustments, but allow auto-EPAP settings for patients with comorbid OSA? More importantly, how do we get these patients, who do not fit in any of the specified insurance criteria for PAP therapy approved for treatment?

A uniform diagnostic definition and clear taxonomy allows for resource allocation, from government funded grants for clinical trials to a better-informed distribution of health care systems resources and support health care policy changes to improve patient-centric outcomes. Here, we propose that the morbidly obese patient (BMI >40 kg/m2) with chronic airflow obstruction and a forced expiratory ratio (FEV₁/FVC) <0.7 with awake daytime hypercapnia (PaCO₂ > 45 mm Hg) represents a different entity/phenotype and fits best under the triple overlap syndrome taxonomy.

We suspect that these patients have worse outcomes, including comorbidity burden, quality of life, exacerbation rates, longer hospital length-of-stay, and respiratory and all-cause mortality. Large, multicenter, controlled trials comparing the long-term effectiveness of NIV and CPAP: measurements of respiratory function, gas exchange, blood pressure, and health related quality of life are needed. This is a group of patients that may specifically benefit from volume-targeted pressure support mode ventilation with auto-EPAP capabilities upon discharge from the hospital after an acute exacerbation.
 

Inpatient (sleep medicine) and outpatient transitions

In patients hospitalized with the triple overlap syndrome, there are certain considerations that are of special interest. Given comorbid hypercapnia and limited data on NIV superiority over CPAP, a sleep study should not be needed for NIV qualification. In addition, the medical team may consider the following (Figure 1):

162136_fig1_web.jpg

1. Noninvasive Ventilation:

a. Maintaining a high-pressure support differential between inspiratory positive airway pressure (IPAP) and EPAP. This can usually be achieved at 8-10 cm H₂O, further adjusting to target a tidal volume (Vt) of 8 mL/kg of ideal body weight (IBW).

b. Higher EPAP: To overcome dependent atelectasis, improve ventilation-perfusion (VQ) matching, and better treat upper airway resistance both during wakefulness and sleep. Also, adjustments of EPAP at bedside should be considered to counteract auto-PEEP-related ineffective triggering if observed.

c. OSA screening and EPAP adjustment: for high residual obstructive apneas or hypopneas if data are available on the NIV device, or with the use of peripheral arterial tonometry sleep testing devices with NIV on overnight before discharge.

d. Does the patient meet criteria for oxygen supplementation at home? Wean oxygen off, if possible.

2. Case-managers can help establish services with a durable medical equipment provider with expertise in advanced PAP devices.3. Obesity management, Consider referral to an obesity management program for lifestyle/dietary modifications along with pharmacotherapy or bariatric surgery interventions.

4. Close follow-up, track exacerbations. Device download data are crucial to monitor adherence/tolerance and treatment effectiveness with particular interest in AHI, oximetry, and CO₂ trends monitoring. Some patients may need dedicated titration polysomnograms to adjust ventilation settings, for optimization of residual OSA or for oxygen addition or discontinuation.
 

Conclusion

Patients with the triple overlap phenotype have not been systematically defined, studied, or included in clinical trials. We anticipate that these patients have worse outcomes: quality of life, symptom and comorbidity burden, exacerbation rates, in-hospital mortality, longer hospital stay and ICU stay, and respiratory and all-cause mortality. This is a group of patients that may specifically benefit from domiciliary NIV set-up upon discharge from the hospital with close follow-up. Properly identifying these patients will help pulmonologists and health care systems direct resources to optimally manage this complex group of patients. Funding of research trials to support clinical guidelines development should be prioritized. Triple overlap syndrome is different from COPD-OSA overlap, OHS with moderate to severe OSA, or OHS without significant OSA.

In our current society, it is likely that the “skinny patient with COPD” who walks into your clinic is less and less your “traditional” patient with COPD. We are seeing in our health care systems more of the “blue bloaters” – patients with COPD and significant obesity. This phenotype is representing what we are seeing worldwide as a consequence of the rising obesity prevalence. In the United States, the prepandemic (2017-2020) estimated percentage of adults over the age of 40 with obesity, defined as a body mass index (BMI) of at least 30 kg/m², was over 40%. Moreover, the estimated percentage of adults with morbid obesity (BMI at least 40 kg/m₂) is close to 10% (Akinbami, LJ et al. Vital Health Stat. 2022:190:1-36) and trending up. These patients with the “triple overlap” of morbid obesity, COPD, and awake daytime hypercapnia are being seen in clinics and in-hospital settings with increasing frequency, often presenting with complicating comorbidities such as acute respiratory failure, acute heart failure, kidney disease, or pulmonary hypertension. We are now faced with managing these patients with complex disease.

The obesity paradox does not seem applicable in the triple overlap phenotype. Patients with COPD who are overweight, defined as “mild obesity,” have lower mortality when compared with normal weight and underweight patients with COPD; however, this effect diminishes when BMI increases beyond 32 kg/m². With increasing obesity severity and aging, the risk of both obstructive sleep apnea (OSA) and hypoventilation increases. It is well documented that COPD-OSA overlap is linked to worse outcomes and that continuous positive airway pressure (CPAP) as first-line therapy decreases readmission rates and mortality. The triple overlap phenotypic patients, however, are presenting with chronic hypercapnic respiratory failure in a backdrop of morbid obesity, unlike the stable COPD-OSA overlap. The pathophysiology of hypoventilation in obesity is complex and multifactorial, and, although significant overlaps likely exist with comorbid COPD, by current definitions, to establish a diagnosis of obesity hypoventilation syndrome (OHS), one must have excluded other causes of hypoventilation, such as COPD.

162136_graphic_web.png

These patients with the triple overlap of morbid obesity, awake daytime hypercapnia, and COPD are the subset of patients that providers struggle to fit in a diagnosis or in clinical research trials.
 

The triple overlap is a distinct syndrome

Different labels have been used in the medical literature: hypercapnic OSA-COPD overlap, morbid obesity and OSA-COPD overlap, hypercapnic morbidly obese COPD and OHS-COPD overlap. A better characterization of this distinctive phenotype is much needed. Patients with OSA-COPD overlap, for example, have an increased propensity to develop hypercapnia at higher FEV₁ when compared with COPD without OSA – but this is thought to be a consequence of prolonged and frequent apneas and hypopneas compounded with obesity-related central hypoventilation. We found that morbidly obese patients with OSA-COPD overlap have a higher hypoxia burden, more severe OSA, and are frequently prescribed noninvasive ventilation after a failed titration polysomnogram (Htun ZM, et al. Am J Respir Crit Care Med. 2019;199:A1382), perhaps signaling a distinctive phenotype with worse outcomes, but the study had the inherent limitations of a single-center, retrospective design lacking data on awake hypercapnia. On the other side, the term OHS-COPD is contradictory and confusing based on current OHS diagnostic criteria.

In standardizing diagnostic criteria for patients with this triple overlap syndrome, challenges remain: would the patient with a BMI of 70 kg/m² and fixed chronic airflow obstruction with FEV₁ 72% fall under the category of hypercapnic COPD vs OHS? Do these patients have worse outcomes regardless of their predominant feature? Would outcomes change if the apnea hypopnea index (AHI) is 10/h vs 65/h? More importantly, do patients with the triple overlap of COPD, morbid obesity, and daytime hypercapnia have worse outcomes when compared with hypercapnic COPD, or OHS with/without OSA? These questions can be better addressed once we agree on a definition. The patients with triple overlap syndrome have been traditionally excluded from clinical trials: the patient with morbid obesity has been excluded from chronic hypercapnic COPD clinical trials, and the patient with COPD has been excluded from OHS trials.

There are no specific clinical guidelines for this triple overlap phenotype. Positive airway pressure is the mainstay of treatment. CPAP is recommended as first-line therapy for patients with OSA-COPD overlap syndrome, while noninvasive ventilation (NIV) with bilevel positive airway pressure (BPAP) is recommended as first-line for the stable ambulatory hypercapnic patient with COPD. It is unclear if NIV is superior to CPAP in patients with triple overlap syndrome, although recently published data showed greater efficacy in reducing carbon dioxide (PaCO₂) and improving quality of life in a small group of subjects (Zheng et al. J Clin Sleep Med. 2022;18[1]:99-107). To take a step further, the subtleties of NIV set up, such as rise time and minimum inspiratory time, are contradictory: the goal in ventilating patients with COPD is to shorten inspiratory time, prolonging expiratory time, therefore allowing a shortened inspiratory cycle. In obesity, ventilation strategies aim to prolong and sustain inspiratory time to improve ventilation and dependent atelectasis. Another area of uncertainty is device selection. Should we aim to provide a respiratory assist device (RAD): the traditional, rent to own bilevel PAP without auto-expiratory positive airway pressure (EPAP) capabilities and lower maximum inspiratory pressure delivery capacity, vs a home mechanical ventilator at a higher expense, life-time rental, and one-way only data monitoring, which limits remote prescription adjustments, but allow auto-EPAP settings for patients with comorbid OSA? More importantly, how do we get these patients, who do not fit in any of the specified insurance criteria for PAP therapy approved for treatment?

A uniform diagnostic definition and clear taxonomy allows for resource allocation, from government funded grants for clinical trials to a better-informed distribution of health care systems resources and support health care policy changes to improve patient-centric outcomes. Here, we propose that the morbidly obese patient (BMI >40 kg/m2) with chronic airflow obstruction and a forced expiratory ratio (FEV₁/FVC) <0.7 with awake daytime hypercapnia (PaCO₂ > 45 mm Hg) represents a different entity/phenotype and fits best under the triple overlap syndrome taxonomy.

We suspect that these patients have worse outcomes, including comorbidity burden, quality of life, exacerbation rates, longer hospital length-of-stay, and respiratory and all-cause mortality. Large, multicenter, controlled trials comparing the long-term effectiveness of NIV and CPAP: measurements of respiratory function, gas exchange, blood pressure, and health related quality of life are needed. This is a group of patients that may specifically benefit from volume-targeted pressure support mode ventilation with auto-EPAP capabilities upon discharge from the hospital after an acute exacerbation.
 

Inpatient (sleep medicine) and outpatient transitions

In patients hospitalized with the triple overlap syndrome, there are certain considerations that are of special interest. Given comorbid hypercapnia and limited data on NIV superiority over CPAP, a sleep study should not be needed for NIV qualification. In addition, the medical team may consider the following (Figure 1):

162136_fig1_web.jpg

1. Noninvasive Ventilation:

a. Maintaining a high-pressure support differential between inspiratory positive airway pressure (IPAP) and EPAP. This can usually be achieved at 8-10 cm H₂O, further adjusting to target a tidal volume (Vt) of 8 mL/kg of ideal body weight (IBW).

b. Higher EPAP: To overcome dependent atelectasis, improve ventilation-perfusion (VQ) matching, and better treat upper airway resistance both during wakefulness and sleep. Also, adjustments of EPAP at bedside should be considered to counteract auto-PEEP-related ineffective triggering if observed.

c. OSA screening and EPAP adjustment: for high residual obstructive apneas or hypopneas if data are available on the NIV device, or with the use of peripheral arterial tonometry sleep testing devices with NIV on overnight before discharge.

d. Does the patient meet criteria for oxygen supplementation at home? Wean oxygen off, if possible.

2. Case-managers can help establish services with a durable medical equipment provider with expertise in advanced PAP devices.3. Obesity management, Consider referral to an obesity management program for lifestyle/dietary modifications along with pharmacotherapy or bariatric surgery interventions.

4. Close follow-up, track exacerbations. Device download data are crucial to monitor adherence/tolerance and treatment effectiveness with particular interest in AHI, oximetry, and CO₂ trends monitoring. Some patients may need dedicated titration polysomnograms to adjust ventilation settings, for optimization of residual OSA or for oxygen addition or discontinuation.
 

Conclusion

Patients with the triple overlap phenotype have not been systematically defined, studied, or included in clinical trials. We anticipate that these patients have worse outcomes: quality of life, symptom and comorbidity burden, exacerbation rates, in-hospital mortality, longer hospital stay and ICU stay, and respiratory and all-cause mortality. This is a group of patients that may specifically benefit from domiciliary NIV set-up upon discharge from the hospital with close follow-up. Properly identifying these patients will help pulmonologists and health care systems direct resources to optimally manage this complex group of patients. Funding of research trials to support clinical guidelines development should be prioritized. Triple overlap syndrome is different from COPD-OSA overlap, OHS with moderate to severe OSA, or OHS without significant OSA.

Estimates suggest that nearly 1 billion adults worldwide could have sleep apnea (Benjafield AV, et al. Lancet Respir Med. 2019;7[8]:687-698). Even with the current widespread use of portable sleep testing, cheap and innovative models of OSA care will need to be developed to address this growing epidemic. This fact is particularly true for communities with significant health disparities, as the evidence suggests diagnostic rates for OSA are extremely poor in these areas (Stansbury R, et al. J Clin Sleep Med. 2022;18[3]:817-824). Current models of care for OSA are predominantly outpatient based. Hospital sleep medicine offers a potential mechanism to capture patients with OSA who would otherwise go undiagnosed and potentially suffer adverse health outcomes from untreated disease.

What is hospital sleep medicine?

Hospital sleep medicine includes the evaluation and management of sleep disorders, including, but not limited to, insomnia, restless legs syndrome, and circadian rhythm disorders, in hospitalized patients. Our program centers around proactive screening and early recognition of sleep-disordered breathing (SDB). Patients at high risk for SDB are identified upon entry to the hospital. These individuals are educated about the disease process and how it impacts comorbid health conditions. Recommendations are provided to the primary team regarding the appropriate screening test for SDB; positive airway pressure trials; mask fitting and acclimation; and coordination with care management in the discharge process, including scheduling follow-up care and diagnostic sleep studies. This program has become an integral part of our comprehensive sleep program, which includes inpatient, outpatient, and sleep center care and utilizes a multidisciplinary team approach including sleep specialists, sleep technologists, respiratory therapists, nurses, information technology professionals, and discharge planners, as well as ambulatory sleep clinics and sleep laboratories.

Evidence for hospital sleep medicine

While there has been interest in hospital-based sleep medicine since 2000, the most well-validated clinical pathway was first described by Sharma and colleagues in 2015 (Sharma, et al. J Clin Sleep Med. 2015;11[7]:717-723). This initial application of a formal sleep program demonstrated a high prevalence of SDB in hospitalized adult patients and led to a substantial increase in SDB diagnoses in the system. Subsequent studies have demonstrated improved outcomes, particularly in patients with cardiopulmonary disease. For example, there are data to suggest that hospitalized patients with congestive heart failure or COPD have increased rates of readmission, and early diagnosis and intervention are associated with decreased rates of subsequent readmission and ED visits (Konikkara J, et al. Hosp Pract. 2016;44[1]:41-47; Sharma S, et al. Am J Cardiol. 2016;117[6]:940-945). Long-term data also suggest survival benefit (Sharma S, et al. Am J Med. 2017;130[10]:1184-1191). Adherence to inpatient PAP trials has also been shown to predict outpatient follow-up and adherence to PAP therapy (Sharma S, et al. Sleep Breath. 2022; published online June 18, 2022).

Establishing a team

Establishing a hospital sleep medicine program requires upfront investment and training and begins with educating key stakeholders. Support from executive administration and various departments including respiratory, sleep medicine, information technology, nursing, physicians, mid-level providers, and discharge planning is essential. Data are available, as outlined here, showing significant improvement in patient outcomes with a hospital sleep medicine program. This information can garner significant enthusiasm from leadership to support the initiation of a program. A more detailed account of key program elements, inpatient protocols, and technologies utilized is available in our recent review (Sharma S, Stansbury R. Chest. 2022;161[4]:1083-1091). Table 1 from this article is highlighted here and outlines the essential components (SEAT-COM) of our hospital sleep medicine model. While each component of this model is important, we stress the importance of care coordination, timely diagnostic testing, and treatment, as significant delays can lead to inadequate time for acclimatization and optimization of therapy. It is important to note that the practice of hospital sleep medicine does not supplant clinic-based approaches, but rather serves to facilitate and enhance outpatient diagnosis and treatment.

160606_graphic_web.jpg

Current questions

Data to date suggest a hospital sleep medicine program positively influences important clinical endpoints in hospitalized patients identified to be at risk for SDB. However, much of the published research is based on retrospective and prospective analysis of established clinical programs. Further, most studies have been completed at large, urban-based academic medical centers. Our group has recently completed a validation study in our local rural population, but larger multicenter trials involving more diverse communities and health systems are needed to better understand outcomes and further refine the optimal timing of screening and intervention for SDB in hospitalized patients (Stansbury, et al. Sleep Breath. 2022; published online January 20, 2022).

A common question that arises is the program’s impact regarding payment for rendered service in the context of Medicare’s prospective payment system. Given that the program focuses on screening for SDB and does not utilize formal testing for diagnosis, there is no additional cost for diagnostic tests or procedural codes. Thus, the diagnosis-related group is not impacted (Sharma S, Stansbury R. Chest. 2022;161[4]:1083-1091). Importantly, hospital sleep medicine has the potential for cost savings given the reduction in hospital readmissions and decreased adverse events during a patient’s hospital stay. The economics of the initial investment in a hospital sleep program versus potential savings from improved patient outcomes warrants evaluation.
 

Conclusion

SDB is a prevalent disorder with potential deleterious impacts on a patient’s health. Despite this, it is underrecognized and, thus, undertreated. Hospital sleep medicine is a growing model of care that may expand our capability for early diagnosis and intervention. Studies have demonstrated benefits to patients, particularly those with cardiopulmonary disease. However, additional studies are required to further validate hospital-based sleep medicine in more diverse populations and environments.

Dr. Del Prado Rico and Dr. Stansbury are with the Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Health Science Center North, West Virginia University. Dr. Stansbury is also with the Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh.

Estimates suggest that nearly 1 billion adults worldwide could have sleep apnea (Benjafield AV, et al. Lancet Respir Med. 2019;7[8]:687-698). Even with the current widespread use of portable sleep testing, cheap and innovative models of OSA care will need to be developed to address this growing epidemic. This fact is particularly true for communities with significant health disparities, as the evidence suggests diagnostic rates for OSA are extremely poor in these areas (Stansbury R, et al. J Clin Sleep Med. 2022;18[3]:817-824). Current models of care for OSA are predominantly outpatient based. Hospital sleep medicine offers a potential mechanism to capture patients with OSA who would otherwise go undiagnosed and potentially suffer adverse health outcomes from untreated disease.

What is hospital sleep medicine?

Hospital sleep medicine includes the evaluation and management of sleep disorders, including, but not limited to, insomnia, restless legs syndrome, and circadian rhythm disorders, in hospitalized patients. Our program centers around proactive screening and early recognition of sleep-disordered breathing (SDB). Patients at high risk for SDB are identified upon entry to the hospital. These individuals are educated about the disease process and how it impacts comorbid health conditions. Recommendations are provided to the primary team regarding the appropriate screening test for SDB; positive airway pressure trials; mask fitting and acclimation; and coordination with care management in the discharge process, including scheduling follow-up care and diagnostic sleep studies. This program has become an integral part of our comprehensive sleep program, which includes inpatient, outpatient, and sleep center care and utilizes a multidisciplinary team approach including sleep specialists, sleep technologists, respiratory therapists, nurses, information technology professionals, and discharge planners, as well as ambulatory sleep clinics and sleep laboratories.

Evidence for hospital sleep medicine

While there has been interest in hospital-based sleep medicine since 2000, the most well-validated clinical pathway was first described by Sharma and colleagues in 2015 (Sharma, et al. J Clin Sleep Med. 2015;11[7]:717-723). This initial application of a formal sleep program demonstrated a high prevalence of SDB in hospitalized adult patients and led to a substantial increase in SDB diagnoses in the system. Subsequent studies have demonstrated improved outcomes, particularly in patients with cardiopulmonary disease. For example, there are data to suggest that hospitalized patients with congestive heart failure or COPD have increased rates of readmission, and early diagnosis and intervention are associated with decreased rates of subsequent readmission and ED visits (Konikkara J, et al. Hosp Pract. 2016;44[1]:41-47; Sharma S, et al. Am J Cardiol. 2016;117[6]:940-945). Long-term data also suggest survival benefit (Sharma S, et al. Am J Med. 2017;130[10]:1184-1191). Adherence to inpatient PAP trials has also been shown to predict outpatient follow-up and adherence to PAP therapy (Sharma S, et al. Sleep Breath. 2022; published online June 18, 2022).

Establishing a team

Establishing a hospital sleep medicine program requires upfront investment and training and begins with educating key stakeholders. Support from executive administration and various departments including respiratory, sleep medicine, information technology, nursing, physicians, mid-level providers, and discharge planning is essential. Data are available, as outlined here, showing significant improvement in patient outcomes with a hospital sleep medicine program. This information can garner significant enthusiasm from leadership to support the initiation of a program. A more detailed account of key program elements, inpatient protocols, and technologies utilized is available in our recent review (Sharma S, Stansbury R. Chest. 2022;161[4]:1083-1091). Table 1 from this article is highlighted here and outlines the essential components (SEAT-COM) of our hospital sleep medicine model. While each component of this model is important, we stress the importance of care coordination, timely diagnostic testing, and treatment, as significant delays can lead to inadequate time for acclimatization and optimization of therapy. It is important to note that the practice of hospital sleep medicine does not supplant clinic-based approaches, but rather serves to facilitate and enhance outpatient diagnosis and treatment.

160606_graphic_web.jpg

Current questions

Data to date suggest a hospital sleep medicine program positively influences important clinical endpoints in hospitalized patients identified to be at risk for SDB. However, much of the published research is based on retrospective and prospective analysis of established clinical programs. Further, most studies have been completed at large, urban-based academic medical centers. Our group has recently completed a validation study in our local rural population, but larger multicenter trials involving more diverse communities and health systems are needed to better understand outcomes and further refine the optimal timing of screening and intervention for SDB in hospitalized patients (Stansbury, et al. Sleep Breath. 2022; published online January 20, 2022).

A common question that arises is the program’s impact regarding payment for rendered service in the context of Medicare’s prospective payment system. Given that the program focuses on screening for SDB and does not utilize formal testing for diagnosis, there is no additional cost for diagnostic tests or procedural codes. Thus, the diagnosis-related group is not impacted (Sharma S, Stansbury R. Chest. 2022;161[4]:1083-1091). Importantly, hospital sleep medicine has the potential for cost savings given the reduction in hospital readmissions and decreased adverse events during a patient’s hospital stay. The economics of the initial investment in a hospital sleep program versus potential savings from improved patient outcomes warrants evaluation.
 

Conclusion

SDB is a prevalent disorder with potential deleterious impacts on a patient’s health. Despite this, it is underrecognized and, thus, undertreated. Hospital sleep medicine is a growing model of care that may expand our capability for early diagnosis and intervention. Studies have demonstrated benefits to patients, particularly those with cardiopulmonary disease. However, additional studies are required to further validate hospital-based sleep medicine in more diverse populations and environments.

Dr. Del Prado Rico and Dr. Stansbury are with the Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Health Science Center North, West Virginia University. Dr. Stansbury is also with the Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh.

Estimates suggest that nearly 1 billion adults worldwide could have sleep apnea (Benjafield AV, et al. Lancet Respir Med. 2019;7[8]:687-698). Even with the current widespread use of portable sleep testing, cheap and innovative models of OSA care will need to be developed to address this growing epidemic. This fact is particularly true for communities with significant health disparities, as the evidence suggests diagnostic rates for OSA are extremely poor in these areas (Stansbury R, et al. J Clin Sleep Med. 2022;18[3]:817-824). Current models of care for OSA are predominantly outpatient based. Hospital sleep medicine offers a potential mechanism to capture patients with OSA who would otherwise go undiagnosed and potentially suffer adverse health outcomes from untreated disease.

What is hospital sleep medicine?

Hospital sleep medicine includes the evaluation and management of sleep disorders, including, but not limited to, insomnia, restless legs syndrome, and circadian rhythm disorders, in hospitalized patients. Our program centers around proactive screening and early recognition of sleep-disordered breathing (SDB). Patients at high risk for SDB are identified upon entry to the hospital. These individuals are educated about the disease process and how it impacts comorbid health conditions. Recommendations are provided to the primary team regarding the appropriate screening test for SDB; positive airway pressure trials; mask fitting and acclimation; and coordination with care management in the discharge process, including scheduling follow-up care and diagnostic sleep studies. This program has become an integral part of our comprehensive sleep program, which includes inpatient, outpatient, and sleep center care and utilizes a multidisciplinary team approach including sleep specialists, sleep technologists, respiratory therapists, nurses, information technology professionals, and discharge planners, as well as ambulatory sleep clinics and sleep laboratories.

Evidence for hospital sleep medicine

While there has been interest in hospital-based sleep medicine since 2000, the most well-validated clinical pathway was first described by Sharma and colleagues in 2015 (Sharma, et al. J Clin Sleep Med. 2015;11[7]:717-723). This initial application of a formal sleep program demonstrated a high prevalence of SDB in hospitalized adult patients and led to a substantial increase in SDB diagnoses in the system. Subsequent studies have demonstrated improved outcomes, particularly in patients with cardiopulmonary disease. For example, there are data to suggest that hospitalized patients with congestive heart failure or COPD have increased rates of readmission, and early diagnosis and intervention are associated with decreased rates of subsequent readmission and ED visits (Konikkara J, et al. Hosp Pract. 2016;44[1]:41-47; Sharma S, et al. Am J Cardiol. 2016;117[6]:940-945). Long-term data also suggest survival benefit (Sharma S, et al. Am J Med. 2017;130[10]:1184-1191). Adherence to inpatient PAP trials has also been shown to predict outpatient follow-up and adherence to PAP therapy (Sharma S, et al. Sleep Breath. 2022; published online June 18, 2022).

Establishing a team

Establishing a hospital sleep medicine program requires upfront investment and training and begins with educating key stakeholders. Support from executive administration and various departments including respiratory, sleep medicine, information technology, nursing, physicians, mid-level providers, and discharge planning is essential. Data are available, as outlined here, showing significant improvement in patient outcomes with a hospital sleep medicine program. This information can garner significant enthusiasm from leadership to support the initiation of a program. A more detailed account of key program elements, inpatient protocols, and technologies utilized is available in our recent review (Sharma S, Stansbury R. Chest. 2022;161[4]:1083-1091). Table 1 from this article is highlighted here and outlines the essential components (SEAT-COM) of our hospital sleep medicine model. While each component of this model is important, we stress the importance of care coordination, timely diagnostic testing, and treatment, as significant delays can lead to inadequate time for acclimatization and optimization of therapy. It is important to note that the practice of hospital sleep medicine does not supplant clinic-based approaches, but rather serves to facilitate and enhance outpatient diagnosis and treatment.

160606_graphic_web.jpg

Current questions

Data to date suggest a hospital sleep medicine program positively influences important clinical endpoints in hospitalized patients identified to be at risk for SDB. However, much of the published research is based on retrospective and prospective analysis of established clinical programs. Further, most studies have been completed at large, urban-based academic medical centers. Our group has recently completed a validation study in our local rural population, but larger multicenter trials involving more diverse communities and health systems are needed to better understand outcomes and further refine the optimal timing of screening and intervention for SDB in hospitalized patients (Stansbury, et al. Sleep Breath. 2022; published online January 20, 2022).

A common question that arises is the program’s impact regarding payment for rendered service in the context of Medicare’s prospective payment system. Given that the program focuses on screening for SDB and does not utilize formal testing for diagnosis, there is no additional cost for diagnostic tests or procedural codes. Thus, the diagnosis-related group is not impacted (Sharma S, Stansbury R. Chest. 2022;161[4]:1083-1091). Importantly, hospital sleep medicine has the potential for cost savings given the reduction in hospital readmissions and decreased adverse events during a patient’s hospital stay. The economics of the initial investment in a hospital sleep program versus potential savings from improved patient outcomes warrants evaluation.
 

Conclusion

SDB is a prevalent disorder with potential deleterious impacts on a patient’s health. Despite this, it is underrecognized and, thus, undertreated. Hospital sleep medicine is a growing model of care that may expand our capability for early diagnosis and intervention. Studies have demonstrated benefits to patients, particularly those with cardiopulmonary disease. However, additional studies are required to further validate hospital-based sleep medicine in more diverse populations and environments.

Dr. Del Prado Rico and Dr. Stansbury are with the Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Health Science Center North, West Virginia University. Dr. Stansbury is also with the Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh.

Obstructive sleep apnea is a prevalent and underdiagnosed sleep-related breathing disorder. The estimated prevalence of OSA in the general population of North America ranges from 9% to 38%. This prevalence is higher in men, with a roughly 2:1 male to female ratio, and it also increases with age (Senaratna CV, et al. Sleep Med Rev. 2017;34:70-81). In large epidemiologic studies, the association between OSA and atrial fibrillation (AF) has been well established. The prevalence of OSA in patients with AF is high, with estimates ranging from 21% to 74%. In the OSA population, the Sleep Heart Health Study (Mehra R, et al. Am J Respir Crit Care Med. 2006;173[8]:910-16) and the Multi Ethnic Study of Atherosclerosis (Lin GM, et al. Am J Epidemiol. 2015;182[1]:49-57) found that patients with OSA had a twofold to fourfold increased risk of AF compared with those who did not have OSA. Therefore, the most current American Heart Association guidelines recommend assessing OSA symptoms in all patients with AF and screening for OSA in recurrent patients with AF.

The pathophysiology of OSA involves multiple physiologic stressors that may contribute to an increased propensity for atrial arrhythmias in this population. Among these factors are large changes in intrathoracic pressures that may cause atrial and ventricular wall stretching, recurrent oxidative stress, and a sympathetic surge associated with shortening atrial refractory periods and atrial extrasystoles. By occurring nightly over many years, these physiologic stressors may lead to permanent atrial dilation and structural remodeling, eventually affecting the conduction system and producing a substrate conducive to reentrant circuits. Other common comorbidities in patients with OSA–such as hypertension, obesity, and metabolic syndrome–may also contribute to arrhythmogenicity (Linz D, et al. JAMA Cardiol. 2018;3[6]:532).

Mudrakola_Harsha_V_web.jpg

Does treating OSA with CPAP prevent the development of AF?

Previous case-control and retrospective observational studies suggested that having OSA makes treating AF more difficult. Patients with OSA had lower response rates to antiarrhythmic drugs, with the lowest in those with more severe OSA. Rhythm control with cardioversion and catheter-based pulmonary vein isolation was also less successful in patients with OSA due to higher rates of AF recurrence. According to one meta-analysis, patients with OSA had a 31% higher rate of AF recurrence after pulmonary vein isolation (Li L, et al. Europace. 2014;16[9]:1309-14).

Prospective studies using CPAP to treat OSA have not demonstrated a reduced risk of adverse cardiovascular outcomes. The SAVE trial is the most well-known of these studies. The primary endpoint was death from cardiovascular causes (myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack). There was no difference in this outcome between the CPAP and usual care groups. A secondary outcome in this study was new-onset AF detected by electrocardiography, and there was no difference between the CPAP and the usual care group. The low amount of CPAP usage in the treatment group was a commonly cited shortcoming of the SAVE trial–mean usage was 4.4 hours per night during the first month of treatment and subsequently decreased to 3.3 hours per night by the 12-month time point (McEvoy RD, et al. N Engl J Med. 2016;375[10]:919-31).

Caples and colleagues screened patients undergoing direct current cardioversion or catheter ablation. They chose those who were also positive for OSA by polysomnography (apnea-hypopnea index – AHI greater than five events per hour). Twenty-five patients were included in the study and were randomly assigned to either CPAP treatment or usual care. Body mass index, blood pressure, ejection fraction, AHI, and nocturnal desaturation levels were comparable between the two groups. The rate of recurrence of AF and the time point following randomization at which the AF recurred did not differ between the two groups (Caples SM, et al. Int J Cardiol. 2019;278:133-6).

A Norwegian trial by Traaen and colleagues included a larger sample of 108 patients with moderate to severe sleep apnea and paroxysmal AF who underwent catheter ablation. Patients were followed for 5 months before and 12 months after ablation. They were randomly assigned to either CPAP therapy plus usual care or usual care alone. The primary goal was to assess AF burden using implanted loop recorders. There was no significant difference in AF burden between the two groups from baseline to the final 3 months of the study (Traaen GM, et al. Am J Respir Crit Care Med. 2021;204[5]:573-82). These two prospective trials, which had AF recurrence or burden as primary outcomes, found no interaction between AF burden and CPAP use, at least within the first year of therapy. Both trials found that their participants used CPAP for more extended periods of time than the SAVE trial, with over 6 hours in the Caples and coworkers’ trial and nearly 5 hours in the Traaen and coworkers’ study.
 

Is the lack of efficacy due to starting CPAP too late in the course of OSA?

It has been proposed that there may be a critical early period after the onset of OSA when intervention with CPAP (or alternative therapies) will be most effective in preventing adverse cardiovascular outcomes. An answer will almost certainly necessitate a long-term prospective study enrolling people before they develop OSA. Additionally, the AHI is used in most trials to determine the presence and severity of OSA. However, the AHI has been shown to have a poor correlation with sleep-related symptoms, and it may fail to capture key OSA pathophysiologic stressors (e.g., hyperadrenergic drive, cyclical hypoxemia, etc), which may increase the risk of AF. Other disease characteristics and polysomnographic features may better capture disease severity and the cardiovascular risk factors associated with it. The respiratory arousal threshold, arousal index, degree of loop gain, hypoxic burden, heart rate variability, and cardiopulmonary coupling are some examples of such features.

Another possible explanation is that AF is not causally related, and the demonstrated association between the two is because both conditions share risk factors such as age and BMI, among others. Or, if they are causally linked, OSA may be a minor contributor, and the magnitude of that contribution is insufficient to reduce the risk of AF significantly by treating OSA. More research is needed to define the salient intervenable aspects of OSA better and design the optimal timing and duration of intervention.

Dr. Mudrakola is with the Department of Pulmonary & Critical Care Medicine, Summa Health, Akron, Ohio. Dr. Selim is with the Department of Pulmonary & Critical Care Medicine, Mayo Clinic, Rochester, Minnesota.

Obstructive sleep apnea is a prevalent and underdiagnosed sleep-related breathing disorder. The estimated prevalence of OSA in the general population of North America ranges from 9% to 38%. This prevalence is higher in men, with a roughly 2:1 male to female ratio, and it also increases with age (Senaratna CV, et al. Sleep Med Rev. 2017;34:70-81). In large epidemiologic studies, the association between OSA and atrial fibrillation (AF) has been well established. The prevalence of OSA in patients with AF is high, with estimates ranging from 21% to 74%. In the OSA population, the Sleep Heart Health Study (Mehra R, et al. Am J Respir Crit Care Med. 2006;173[8]:910-16) and the Multi Ethnic Study of Atherosclerosis (Lin GM, et al. Am J Epidemiol. 2015;182[1]:49-57) found that patients with OSA had a twofold to fourfold increased risk of AF compared with those who did not have OSA. Therefore, the most current American Heart Association guidelines recommend assessing OSA symptoms in all patients with AF and screening for OSA in recurrent patients with AF.

The pathophysiology of OSA involves multiple physiologic stressors that may contribute to an increased propensity for atrial arrhythmias in this population. Among these factors are large changes in intrathoracic pressures that may cause atrial and ventricular wall stretching, recurrent oxidative stress, and a sympathetic surge associated with shortening atrial refractory periods and atrial extrasystoles. By occurring nightly over many years, these physiologic stressors may lead to permanent atrial dilation and structural remodeling, eventually affecting the conduction system and producing a substrate conducive to reentrant circuits. Other common comorbidities in patients with OSA–such as hypertension, obesity, and metabolic syndrome–may also contribute to arrhythmogenicity (Linz D, et al. JAMA Cardiol. 2018;3[6]:532).

Mudrakola_Harsha_V_web.jpg

Does treating OSA with CPAP prevent the development of AF?

Previous case-control and retrospective observational studies suggested that having OSA makes treating AF more difficult. Patients with OSA had lower response rates to antiarrhythmic drugs, with the lowest in those with more severe OSA. Rhythm control with cardioversion and catheter-based pulmonary vein isolation was also less successful in patients with OSA due to higher rates of AF recurrence. According to one meta-analysis, patients with OSA had a 31% higher rate of AF recurrence after pulmonary vein isolation (Li L, et al. Europace. 2014;16[9]:1309-14).

Prospective studies using CPAP to treat OSA have not demonstrated a reduced risk of adverse cardiovascular outcomes. The SAVE trial is the most well-known of these studies. The primary endpoint was death from cardiovascular causes (myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack). There was no difference in this outcome between the CPAP and usual care groups. A secondary outcome in this study was new-onset AF detected by electrocardiography, and there was no difference between the CPAP and the usual care group. The low amount of CPAP usage in the treatment group was a commonly cited shortcoming of the SAVE trial–mean usage was 4.4 hours per night during the first month of treatment and subsequently decreased to 3.3 hours per night by the 12-month time point (McEvoy RD, et al. N Engl J Med. 2016;375[10]:919-31).

Caples and colleagues screened patients undergoing direct current cardioversion or catheter ablation. They chose those who were also positive for OSA by polysomnography (apnea-hypopnea index – AHI greater than five events per hour). Twenty-five patients were included in the study and were randomly assigned to either CPAP treatment or usual care. Body mass index, blood pressure, ejection fraction, AHI, and nocturnal desaturation levels were comparable between the two groups. The rate of recurrence of AF and the time point following randomization at which the AF recurred did not differ between the two groups (Caples SM, et al. Int J Cardiol. 2019;278:133-6).

A Norwegian trial by Traaen and colleagues included a larger sample of 108 patients with moderate to severe sleep apnea and paroxysmal AF who underwent catheter ablation. Patients were followed for 5 months before and 12 months after ablation. They were randomly assigned to either CPAP therapy plus usual care or usual care alone. The primary goal was to assess AF burden using implanted loop recorders. There was no significant difference in AF burden between the two groups from baseline to the final 3 months of the study (Traaen GM, et al. Am J Respir Crit Care Med. 2021;204[5]:573-82). These two prospective trials, which had AF recurrence or burden as primary outcomes, found no interaction between AF burden and CPAP use, at least within the first year of therapy. Both trials found that their participants used CPAP for more extended periods of time than the SAVE trial, with over 6 hours in the Caples and coworkers’ trial and nearly 5 hours in the Traaen and coworkers’ study.
 

Is the lack of efficacy due to starting CPAP too late in the course of OSA?

It has been proposed that there may be a critical early period after the onset of OSA when intervention with CPAP (or alternative therapies) will be most effective in preventing adverse cardiovascular outcomes. An answer will almost certainly necessitate a long-term prospective study enrolling people before they develop OSA. Additionally, the AHI is used in most trials to determine the presence and severity of OSA. However, the AHI has been shown to have a poor correlation with sleep-related symptoms, and it may fail to capture key OSA pathophysiologic stressors (e.g., hyperadrenergic drive, cyclical hypoxemia, etc), which may increase the risk of AF. Other disease characteristics and polysomnographic features may better capture disease severity and the cardiovascular risk factors associated with it. The respiratory arousal threshold, arousal index, degree of loop gain, hypoxic burden, heart rate variability, and cardiopulmonary coupling are some examples of such features.

Another possible explanation is that AF is not causally related, and the demonstrated association between the two is because both conditions share risk factors such as age and BMI, among others. Or, if they are causally linked, OSA may be a minor contributor, and the magnitude of that contribution is insufficient to reduce the risk of AF significantly by treating OSA. More research is needed to define the salient intervenable aspects of OSA better and design the optimal timing and duration of intervention.

Dr. Mudrakola is with the Department of Pulmonary & Critical Care Medicine, Summa Health, Akron, Ohio. Dr. Selim is with the Department of Pulmonary & Critical Care Medicine, Mayo Clinic, Rochester, Minnesota.

Obstructive sleep apnea is a prevalent and underdiagnosed sleep-related breathing disorder. The estimated prevalence of OSA in the general population of North America ranges from 9% to 38%. This prevalence is higher in men, with a roughly 2:1 male to female ratio, and it also increases with age (Senaratna CV, et al. Sleep Med Rev. 2017;34:70-81). In large epidemiologic studies, the association between OSA and atrial fibrillation (AF) has been well established. The prevalence of OSA in patients with AF is high, with estimates ranging from 21% to 74%. In the OSA population, the Sleep Heart Health Study (Mehra R, et al. Am J Respir Crit Care Med. 2006;173[8]:910-16) and the Multi Ethnic Study of Atherosclerosis (Lin GM, et al. Am J Epidemiol. 2015;182[1]:49-57) found that patients with OSA had a twofold to fourfold increased risk of AF compared with those who did not have OSA. Therefore, the most current American Heart Association guidelines recommend assessing OSA symptoms in all patients with AF and screening for OSA in recurrent patients with AF.

The pathophysiology of OSA involves multiple physiologic stressors that may contribute to an increased propensity for atrial arrhythmias in this population. Among these factors are large changes in intrathoracic pressures that may cause atrial and ventricular wall stretching, recurrent oxidative stress, and a sympathetic surge associated with shortening atrial refractory periods and atrial extrasystoles. By occurring nightly over many years, these physiologic stressors may lead to permanent atrial dilation and structural remodeling, eventually affecting the conduction system and producing a substrate conducive to reentrant circuits. Other common comorbidities in patients with OSA–such as hypertension, obesity, and metabolic syndrome–may also contribute to arrhythmogenicity (Linz D, et al. JAMA Cardiol. 2018;3[6]:532).

Mudrakola_Harsha_V_web.jpg

Does treating OSA with CPAP prevent the development of AF?

Previous case-control and retrospective observational studies suggested that having OSA makes treating AF more difficult. Patients with OSA had lower response rates to antiarrhythmic drugs, with the lowest in those with more severe OSA. Rhythm control with cardioversion and catheter-based pulmonary vein isolation was also less successful in patients with OSA due to higher rates of AF recurrence. According to one meta-analysis, patients with OSA had a 31% higher rate of AF recurrence after pulmonary vein isolation (Li L, et al. Europace. 2014;16[9]:1309-14).

Prospective studies using CPAP to treat OSA have not demonstrated a reduced risk of adverse cardiovascular outcomes. The SAVE trial is the most well-known of these studies. The primary endpoint was death from cardiovascular causes (myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack). There was no difference in this outcome between the CPAP and usual care groups. A secondary outcome in this study was new-onset AF detected by electrocardiography, and there was no difference between the CPAP and the usual care group. The low amount of CPAP usage in the treatment group was a commonly cited shortcoming of the SAVE trial–mean usage was 4.4 hours per night during the first month of treatment and subsequently decreased to 3.3 hours per night by the 12-month time point (McEvoy RD, et al. N Engl J Med. 2016;375[10]:919-31).

Caples and colleagues screened patients undergoing direct current cardioversion or catheter ablation. They chose those who were also positive for OSA by polysomnography (apnea-hypopnea index – AHI greater than five events per hour). Twenty-five patients were included in the study and were randomly assigned to either CPAP treatment or usual care. Body mass index, blood pressure, ejection fraction, AHI, and nocturnal desaturation levels were comparable between the two groups. The rate of recurrence of AF and the time point following randomization at which the AF recurred did not differ between the two groups (Caples SM, et al. Int J Cardiol. 2019;278:133-6).

A Norwegian trial by Traaen and colleagues included a larger sample of 108 patients with moderate to severe sleep apnea and paroxysmal AF who underwent catheter ablation. Patients were followed for 5 months before and 12 months after ablation. They were randomly assigned to either CPAP therapy plus usual care or usual care alone. The primary goal was to assess AF burden using implanted loop recorders. There was no significant difference in AF burden between the two groups from baseline to the final 3 months of the study (Traaen GM, et al. Am J Respir Crit Care Med. 2021;204[5]:573-82). These two prospective trials, which had AF recurrence or burden as primary outcomes, found no interaction between AF burden and CPAP use, at least within the first year of therapy. Both trials found that their participants used CPAP for more extended periods of time than the SAVE trial, with over 6 hours in the Caples and coworkers’ trial and nearly 5 hours in the Traaen and coworkers’ study.
 

Is the lack of efficacy due to starting CPAP too late in the course of OSA?

It has been proposed that there may be a critical early period after the onset of OSA when intervention with CPAP (or alternative therapies) will be most effective in preventing adverse cardiovascular outcomes. An answer will almost certainly necessitate a long-term prospective study enrolling people before they develop OSA. Additionally, the AHI is used in most trials to determine the presence and severity of OSA. However, the AHI has been shown to have a poor correlation with sleep-related symptoms, and it may fail to capture key OSA pathophysiologic stressors (e.g., hyperadrenergic drive, cyclical hypoxemia, etc), which may increase the risk of AF. Other disease characteristics and polysomnographic features may better capture disease severity and the cardiovascular risk factors associated with it. The respiratory arousal threshold, arousal index, degree of loop gain, hypoxic burden, heart rate variability, and cardiopulmonary coupling are some examples of such features.

Another possible explanation is that AF is not causally related, and the demonstrated association between the two is because both conditions share risk factors such as age and BMI, among others. Or, if they are causally linked, OSA may be a minor contributor, and the magnitude of that contribution is insufficient to reduce the risk of AF significantly by treating OSA. More research is needed to define the salient intervenable aspects of OSA better and design the optimal timing and duration of intervention.

Dr. Mudrakola is with the Department of Pulmonary & Critical Care Medicine, Summa Health, Akron, Ohio. Dr. Selim is with the Department of Pulmonary & Critical Care Medicine, Mayo Clinic, Rochester, Minnesota.

Overview of the problem

Obstructive sleep apnea (OSA) is an extraordinarily common condition impacting nearly 1 billion individuals globally (Benjafield AV, et al. Lancet Respir Med. 2019;7[8]:687). For the past 40 years, the mainstay of treatment has been continuous positive airway pressure (CPAP). However, CPAP usage is highly variable, and not all sleep apnea is created the same with respect to underlying mechanism or patient symptoms. Currently, there is a global CPAP shortage, which has expedited the need for alternative therapies in OSA (Owens RL, et al. Am J Respir Crit Care Med. 2021;204[8]:887). Here, we will provide a broad overview of how individual sleep apnea therapies may be implemented in the sleep clinic and beyond.

Characterizing OSA

First, it is important to understand that sleep apnea emerges for multiple reasons. Some examples include: an excessively collapsible airway, insufficient upper airway reflexes, low arousal threshold (awakening easily to ventilatory disturbance), as well as an unstable chemoreflex system. This list is not comprehensive. However, we believe that the future of OSA management will be targeted therapy for individual OSA traits.

Notably, the patient experience of OSA is also highly variable. Some individuals are excessively sleepy. Some individuals experience OSA as insomnia. Other patients are asymptomatic, but present to the sleep clinic at the behest of a disgruntled bed partner. These individual factors should all be kept in mind when deciding when and how to treat sleep apnea.
 

OSA scoring – past, present, and future

The traditional method for scoring sleep apnea severity is the apnea-hypopnea index (AHI), with mild, moderate, and severe OSA being stratified by the number of events per hour. This metric has shaped many of the modern sleep practices and consensus recommendations but is simply not sophisticated enough to capture the nuance of how or why an individual’s sleep is disrupted from flow-limited breathing. As such, there has been a push in recent times to tailor treatment for OSA to an individual’s physiology. Examples of alternative metrics which quantify sleep apnea traits include the apnea-hypopnea event duration, the sleep apnea-specific hypoxic burden (area under the SpO₂ curve for flow-limited events), as well as the arousal intensity from sleep in the setting of flow-limited breathing. There are numerous other metrics that have been proposed but are beyond the scope of this review (Malhotra A, et al. Sleep. 2021;44[7]:zsab030).

What therapies are available and how can we individualize them to our patients?

As noted, CPAP has been the gold-standard for OSA treatment for 40 years but is not always accepted or tolerated (Malhotra A, et al. Chest. 2018;153[4]:843). Broad categories of OSA management are presented as follows.
 

Surgery for OSA

Upper airway surgery is effective for pediatric OSA treatment, where enlarged tonsils are often the culprit for flow-limited breathing in sleep. For adults, however, there is no one best surgery or surgical candidate. For instance, surgery can be used to improve CPAP tolerance or as a primary OSA treatment. Many individuals with sinus disease may require sinus surgery or septoplasty to improve CPAP tolerability by creating more space for airflow through the nasopharynx. Retrognathic individuals, on the other hand, may benefit from maxillomandibular advancement. Others may benefit from genioglossus advancement or hyoid suspension. The characteristics of the soft palate can be predictive of surgical success with respect to uvulopalatopharyngoplasty (UPPP), with longer uvulas and redundant soft palate tissue being attractive surgical targets. Obviously, this list is far from comprehensive, but Friedman tongue position, tonsil size, and body mass index also appear to be important in predicting surgical success (MacKay S, et al. JAMA. 2020;324[12]:1168).

Hypoglossal nerve stimulation is one surgical treatment option for patients with moderate-severe OSA who are unable or unwilling to use CPAP therapy, have a BMI <32-35 kg/m² (center-dependent), no concentric velopharyngeal collapse on drug-induced sleep endoscopy, and fewer than 25% central/mixed apneas on their sleep study. Areas for further study are whether unilateral or bilateral stimulation are most effective, as well as which of the sleep apnea traits are most predictive of a treatment response (Strohl MM, et al. Curr Sleep Med Rep. 2017;3[3]:133).

Notably, surgical techniques are highly variable, and there are individual patient characteristics, such as lower loop gain (more stable ventilatory control), which may have a greater likelihood of successful upper airway surgery. This is likely because making the upper airway more patent allows for ventilatory overshoots and thereby airway collapse and cyclic, unstable breathing in those with an unstable ventilatory control system. Trials with prespecified surgical techniques based on individual traits are welcome. Additionally, the metrics of a successful surgical treatment for OSA, much like the AHI, are in need of evolution. The Sher criteria, for instance (50% AHI reduction to an AHI < 20/h), are arbitrary, and their clinical utility is unclear.
 

Oral appliances

Oral appliances fall into two broad categories – tongue-retaining devices and mandibular advancement splints (MAS). Of the two, MAS are much more commonly prescribed. Of the MAS devices, custom made devices by an American Academy of Dental Sleep Medicine (AADSM)–trained dentist are recommended over noncustom MAS in the treatment of primary snoring or OSA for those unwilling or unable to wear CPAP. Notably, the 2015 American Academy of Sleep Medicine (AASM) and AADSM shared guidelines were unable to make OSA treatment recommendations based on severity of disease as stratified by the AHI due to the limited quality of evidence. These devices are broadly thought to work by protruding the mandible/tongue and, in-turn, advancing multiple soft tissue components of the velopharynx. Relatively recent work suggests that the following OSA traits are associated with MAS efficacy: lower loop gain, higher arousal threshold, lower ventilatory response to arousal, moderate pharyngeal collapsibility, and weaker upper airway dilator muscle compensation. However, in order for these devices to be successful, close follow-up for titration with a AADSM-certified dentist, as well as a follow-up efficacy sleep study, are recommended. Adherence for custom device use appears to be about 70% use greater than 4 hours per night, with 35% to 40% of those prescribed a device achieving an AHI less than 5/h. Over the counter devices are not routinely recommended, though some practices do use these devices as a trial to see if patients may tolerate custom made devices (Ramar K, et al. J Clin Sleep Med. 2015;11[7]:773).

Upper airway training

Upper airway training has been shown possibly to be effective in treating OSA, though the ideal endotype is still being established. Upper airway training has taken many forms, from woodwind instrument playing, to nocturnal electrical stimulation of the tongue, and, more recently, daytime awake transoral neuromuscular stimulation. These interventions appear to be effective for mild sleep apnea and snoring, but the best training regimen has yet to be established. Equally, as with other routine exercise, there appears to be a “use it or lose it” component, and the ideal maintenance regimen for each of these therapies is yet to be determined.

Weight loss and bariatric surgery

Obesity is a common, reversible risk factor for OSA. However, not all obese individuals develop OSA (typically those with robust upper airway reflexes). Improvements in weight appear to correlate with reductions in tongue fat, which correlate to AHI reduction. Weight loss also creates lower CPAP requirements for many individuals, conceivably improving tolerability. Ongoing work is seeking to understand whether there are changes in upper airway muscle recruitability as well as other change in endotype traits following weight loss surgery.

Pharmacotherapy for OSA

There is a great deal of promise in tailoring pharmacotherapy to individual sleep traits. Acetazolamide, for instance, results in improvements an AHI for both obstructive and central sleep apnea through changes in chemosensitivity and is generally well-tolerated (Schmickl CN, et al. Physiol Rep. 2021;9[20]:e15071). Eszopiclone has been used to raise the arousal threshold for those who awaken from breathing events too easily. With added time, individuals with a low arousal threshold can more effectively recruit upper airway dilator muscles without waking up. Pharmacotherapy to improve upper airway recruitability with combination noradrenergic stimulation and antimuscarinic activity has limited data thus far but may be a useful part of the sleep armamentarium moving forward.

Summary

OSA is a public health priority, and the current global CPAP shortage emphasizes the need for alternative OSA therapies. The ideal therapy for a given patient requires a careful consideration of their individual traits and will be much more refined when endotyping is available in a routine clinical setting. Individualized sleep apnea treatment is the future of sleep medicine and a one-size fits all approach no longer meets the needs of our patients given the current state of sleep medicine knowledge.

Dr. Nokes, Dr. Schmickl, and Dr. Malhotra are with the University of California, San Diego, Division of Pulmonary, Critical Care, and Sleep Medicine, La, Jolla, CA. Dr. Nokes also is with the Veterans Affairs San Diego Healthcare System, sleep section, San Diego, CA. Dr. Vahabzadeh-Hagh is with the University of California, San Diego, Department of Otolaryngology, San Diego, CA.

Overview of the problem

Obstructive sleep apnea (OSA) is an extraordinarily common condition impacting nearly 1 billion individuals globally (Benjafield AV, et al. Lancet Respir Med. 2019;7[8]:687). For the past 40 years, the mainstay of treatment has been continuous positive airway pressure (CPAP). However, CPAP usage is highly variable, and not all sleep apnea is created the same with respect to underlying mechanism or patient symptoms. Currently, there is a global CPAP shortage, which has expedited the need for alternative therapies in OSA (Owens RL, et al. Am J Respir Crit Care Med. 2021;204[8]:887). Here, we will provide a broad overview of how individual sleep apnea therapies may be implemented in the sleep clinic and beyond.

Characterizing OSA

First, it is important to understand that sleep apnea emerges for multiple reasons. Some examples include: an excessively collapsible airway, insufficient upper airway reflexes, low arousal threshold (awakening easily to ventilatory disturbance), as well as an unstable chemoreflex system. This list is not comprehensive. However, we believe that the future of OSA management will be targeted therapy for individual OSA traits.

Notably, the patient experience of OSA is also highly variable. Some individuals are excessively sleepy. Some individuals experience OSA as insomnia. Other patients are asymptomatic, but present to the sleep clinic at the behest of a disgruntled bed partner. These individual factors should all be kept in mind when deciding when and how to treat sleep apnea.
 

OSA scoring – past, present, and future

The traditional method for scoring sleep apnea severity is the apnea-hypopnea index (AHI), with mild, moderate, and severe OSA being stratified by the number of events per hour. This metric has shaped many of the modern sleep practices and consensus recommendations but is simply not sophisticated enough to capture the nuance of how or why an individual’s sleep is disrupted from flow-limited breathing. As such, there has been a push in recent times to tailor treatment for OSA to an individual’s physiology. Examples of alternative metrics which quantify sleep apnea traits include the apnea-hypopnea event duration, the sleep apnea-specific hypoxic burden (area under the SpO₂ curve for flow-limited events), as well as the arousal intensity from sleep in the setting of flow-limited breathing. There are numerous other metrics that have been proposed but are beyond the scope of this review (Malhotra A, et al. Sleep. 2021;44[7]:zsab030).

What therapies are available and how can we individualize them to our patients?

As noted, CPAP has been the gold-standard for OSA treatment for 40 years but is not always accepted or tolerated (Malhotra A, et al. Chest. 2018;153[4]:843). Broad categories of OSA management are presented as follows.
 

Surgery for OSA

Upper airway surgery is effective for pediatric OSA treatment, where enlarged tonsils are often the culprit for flow-limited breathing in sleep. For adults, however, there is no one best surgery or surgical candidate. For instance, surgery can be used to improve CPAP tolerance or as a primary OSA treatment. Many individuals with sinus disease may require sinus surgery or septoplasty to improve CPAP tolerability by creating more space for airflow through the nasopharynx. Retrognathic individuals, on the other hand, may benefit from maxillomandibular advancement. Others may benefit from genioglossus advancement or hyoid suspension. The characteristics of the soft palate can be predictive of surgical success with respect to uvulopalatopharyngoplasty (UPPP), with longer uvulas and redundant soft palate tissue being attractive surgical targets. Obviously, this list is far from comprehensive, but Friedman tongue position, tonsil size, and body mass index also appear to be important in predicting surgical success (MacKay S, et al. JAMA. 2020;324[12]:1168).

Hypoglossal nerve stimulation is one surgical treatment option for patients with moderate-severe OSA who are unable or unwilling to use CPAP therapy, have a BMI <32-35 kg/m² (center-dependent), no concentric velopharyngeal collapse on drug-induced sleep endoscopy, and fewer than 25% central/mixed apneas on their sleep study. Areas for further study are whether unilateral or bilateral stimulation are most effective, as well as which of the sleep apnea traits are most predictive of a treatment response (Strohl MM, et al. Curr Sleep Med Rep. 2017;3[3]:133).

Notably, surgical techniques are highly variable, and there are individual patient characteristics, such as lower loop gain (more stable ventilatory control), which may have a greater likelihood of successful upper airway surgery. This is likely because making the upper airway more patent allows for ventilatory overshoots and thereby airway collapse and cyclic, unstable breathing in those with an unstable ventilatory control system. Trials with prespecified surgical techniques based on individual traits are welcome. Additionally, the metrics of a successful surgical treatment for OSA, much like the AHI, are in need of evolution. The Sher criteria, for instance (50% AHI reduction to an AHI < 20/h), are arbitrary, and their clinical utility is unclear.
 

Oral appliances

Oral appliances fall into two broad categories – tongue-retaining devices and mandibular advancement splints (MAS). Of the two, MAS are much more commonly prescribed. Of the MAS devices, custom made devices by an American Academy of Dental Sleep Medicine (AADSM)–trained dentist are recommended over noncustom MAS in the treatment of primary snoring or OSA for those unwilling or unable to wear CPAP. Notably, the 2015 American Academy of Sleep Medicine (AASM) and AADSM shared guidelines were unable to make OSA treatment recommendations based on severity of disease as stratified by the AHI due to the limited quality of evidence. These devices are broadly thought to work by protruding the mandible/tongue and, in-turn, advancing multiple soft tissue components of the velopharynx. Relatively recent work suggests that the following OSA traits are associated with MAS efficacy: lower loop gain, higher arousal threshold, lower ventilatory response to arousal, moderate pharyngeal collapsibility, and weaker upper airway dilator muscle compensation. However, in order for these devices to be successful, close follow-up for titration with a AADSM-certified dentist, as well as a follow-up efficacy sleep study, are recommended. Adherence for custom device use appears to be about 70% use greater than 4 hours per night, with 35% to 40% of those prescribed a device achieving an AHI less than 5/h. Over the counter devices are not routinely recommended, though some practices do use these devices as a trial to see if patients may tolerate custom made devices (Ramar K, et al. J Clin Sleep Med. 2015;11[7]:773).

Upper airway training

Upper airway training has been shown possibly to be effective in treating OSA, though the ideal endotype is still being established. Upper airway training has taken many forms, from woodwind instrument playing, to nocturnal electrical stimulation of the tongue, and, more recently, daytime awake transoral neuromuscular stimulation. These interventions appear to be effective for mild sleep apnea and snoring, but the best training regimen has yet to be established. Equally, as with other routine exercise, there appears to be a “use it or lose it” component, and the ideal maintenance regimen for each of these therapies is yet to be determined.

Weight loss and bariatric surgery

Obesity is a common, reversible risk factor for OSA. However, not all obese individuals develop OSA (typically those with robust upper airway reflexes). Improvements in weight appear to correlate with reductions in tongue fat, which correlate to AHI reduction. Weight loss also creates lower CPAP requirements for many individuals, conceivably improving tolerability. Ongoing work is seeking to understand whether there are changes in upper airway muscle recruitability as well as other change in endotype traits following weight loss surgery.

Pharmacotherapy for OSA

There is a great deal of promise in tailoring pharmacotherapy to individual sleep traits. Acetazolamide, for instance, results in improvements an AHI for both obstructive and central sleep apnea through changes in chemosensitivity and is generally well-tolerated (Schmickl CN, et al. Physiol Rep. 2021;9[20]:e15071). Eszopiclone has been used to raise the arousal threshold for those who awaken from breathing events too easily. With added time, individuals with a low arousal threshold can more effectively recruit upper airway dilator muscles without waking up. Pharmacotherapy to improve upper airway recruitability with combination noradrenergic stimulation and antimuscarinic activity has limited data thus far but may be a useful part of the sleep armamentarium moving forward.

Summary

OSA is a public health priority, and the current global CPAP shortage emphasizes the need for alternative OSA therapies. The ideal therapy for a given patient requires a careful consideration of their individual traits and will be much more refined when endotyping is available in a routine clinical setting. Individualized sleep apnea treatment is the future of sleep medicine and a one-size fits all approach no longer meets the needs of our patients given the current state of sleep medicine knowledge.

Dr. Nokes, Dr. Schmickl, and Dr. Malhotra are with the University of California, San Diego, Division of Pulmonary, Critical Care, and Sleep Medicine, La, Jolla, CA. Dr. Nokes also is with the Veterans Affairs San Diego Healthcare System, sleep section, San Diego, CA. Dr. Vahabzadeh-Hagh is with the University of California, San Diego, Department of Otolaryngology, San Diego, CA.

Overview of the problem

Obstructive sleep apnea (OSA) is an extraordinarily common condition impacting nearly 1 billion individuals globally (Benjafield AV, et al. Lancet Respir Med. 2019;7[8]:687). For the past 40 years, the mainstay of treatment has been continuous positive airway pressure (CPAP). However, CPAP usage is highly variable, and not all sleep apnea is created the same with respect to underlying mechanism or patient symptoms. Currently, there is a global CPAP shortage, which has expedited the need for alternative therapies in OSA (Owens RL, et al. Am J Respir Crit Care Med. 2021;204[8]:887). Here, we will provide a broad overview of how individual sleep apnea therapies may be implemented in the sleep clinic and beyond.

Characterizing OSA

First, it is important to understand that sleep apnea emerges for multiple reasons. Some examples include: an excessively collapsible airway, insufficient upper airway reflexes, low arousal threshold (awakening easily to ventilatory disturbance), as well as an unstable chemoreflex system. This list is not comprehensive. However, we believe that the future of OSA management will be targeted therapy for individual OSA traits.

Notably, the patient experience of OSA is also highly variable. Some individuals are excessively sleepy. Some individuals experience OSA as insomnia. Other patients are asymptomatic, but present to the sleep clinic at the behest of a disgruntled bed partner. These individual factors should all be kept in mind when deciding when and how to treat sleep apnea.
 

OSA scoring – past, present, and future

The traditional method for scoring sleep apnea severity is the apnea-hypopnea index (AHI), with mild, moderate, and severe OSA being stratified by the number of events per hour. This metric has shaped many of the modern sleep practices and consensus recommendations but is simply not sophisticated enough to capture the nuance of how or why an individual’s sleep is disrupted from flow-limited breathing. As such, there has been a push in recent times to tailor treatment for OSA to an individual’s physiology. Examples of alternative metrics which quantify sleep apnea traits include the apnea-hypopnea event duration, the sleep apnea-specific hypoxic burden (area under the SpO₂ curve for flow-limited events), as well as the arousal intensity from sleep in the setting of flow-limited breathing. There are numerous other metrics that have been proposed but are beyond the scope of this review (Malhotra A, et al. Sleep. 2021;44[7]:zsab030).

What therapies are available and how can we individualize them to our patients?

As noted, CPAP has been the gold-standard for OSA treatment for 40 years but is not always accepted or tolerated (Malhotra A, et al. Chest. 2018;153[4]:843). Broad categories of OSA management are presented as follows.
 

Surgery for OSA

Upper airway surgery is effective for pediatric OSA treatment, where enlarged tonsils are often the culprit for flow-limited breathing in sleep. For adults, however, there is no one best surgery or surgical candidate. For instance, surgery can be used to improve CPAP tolerance or as a primary OSA treatment. Many individuals with sinus disease may require sinus surgery or septoplasty to improve CPAP tolerability by creating more space for airflow through the nasopharynx. Retrognathic individuals, on the other hand, may benefit from maxillomandibular advancement. Others may benefit from genioglossus advancement or hyoid suspension. The characteristics of the soft palate can be predictive of surgical success with respect to uvulopalatopharyngoplasty (UPPP), with longer uvulas and redundant soft palate tissue being attractive surgical targets. Obviously, this list is far from comprehensive, but Friedman tongue position, tonsil size, and body mass index also appear to be important in predicting surgical success (MacKay S, et al. JAMA. 2020;324[12]:1168).

Hypoglossal nerve stimulation is one surgical treatment option for patients with moderate-severe OSA who are unable or unwilling to use CPAP therapy, have a BMI <32-35 kg/m² (center-dependent), no concentric velopharyngeal collapse on drug-induced sleep endoscopy, and fewer than 25% central/mixed apneas on their sleep study. Areas for further study are whether unilateral or bilateral stimulation are most effective, as well as which of the sleep apnea traits are most predictive of a treatment response (Strohl MM, et al. Curr Sleep Med Rep. 2017;3[3]:133).

Notably, surgical techniques are highly variable, and there are individual patient characteristics, such as lower loop gain (more stable ventilatory control), which may have a greater likelihood of successful upper airway surgery. This is likely because making the upper airway more patent allows for ventilatory overshoots and thereby airway collapse and cyclic, unstable breathing in those with an unstable ventilatory control system. Trials with prespecified surgical techniques based on individual traits are welcome. Additionally, the metrics of a successful surgical treatment for OSA, much like the AHI, are in need of evolution. The Sher criteria, for instance (50% AHI reduction to an AHI < 20/h), are arbitrary, and their clinical utility is unclear.
 

Oral appliances

Oral appliances fall into two broad categories – tongue-retaining devices and mandibular advancement splints (MAS). Of the two, MAS are much more commonly prescribed. Of the MAS devices, custom made devices by an American Academy of Dental Sleep Medicine (AADSM)–trained dentist are recommended over noncustom MAS in the treatment of primary snoring or OSA for those unwilling or unable to wear CPAP. Notably, the 2015 American Academy of Sleep Medicine (AASM) and AADSM shared guidelines were unable to make OSA treatment recommendations based on severity of disease as stratified by the AHI due to the limited quality of evidence. These devices are broadly thought to work by protruding the mandible/tongue and, in-turn, advancing multiple soft tissue components of the velopharynx. Relatively recent work suggests that the following OSA traits are associated with MAS efficacy: lower loop gain, higher arousal threshold, lower ventilatory response to arousal, moderate pharyngeal collapsibility, and weaker upper airway dilator muscle compensation. However, in order for these devices to be successful, close follow-up for titration with a AADSM-certified dentist, as well as a follow-up efficacy sleep study, are recommended. Adherence for custom device use appears to be about 70% use greater than 4 hours per night, with 35% to 40% of those prescribed a device achieving an AHI less than 5/h. Over the counter devices are not routinely recommended, though some practices do use these devices as a trial to see if patients may tolerate custom made devices (Ramar K, et al. J Clin Sleep Med. 2015;11[7]:773).

Upper airway training

Upper airway training has been shown possibly to be effective in treating OSA, though the ideal endotype is still being established. Upper airway training has taken many forms, from woodwind instrument playing, to nocturnal electrical stimulation of the tongue, and, more recently, daytime awake transoral neuromuscular stimulation. These interventions appear to be effective for mild sleep apnea and snoring, but the best training regimen has yet to be established. Equally, as with other routine exercise, there appears to be a “use it or lose it” component, and the ideal maintenance regimen for each of these therapies is yet to be determined.

Weight loss and bariatric surgery

Obesity is a common, reversible risk factor for OSA. However, not all obese individuals develop OSA (typically those with robust upper airway reflexes). Improvements in weight appear to correlate with reductions in tongue fat, which correlate to AHI reduction. Weight loss also creates lower CPAP requirements for many individuals, conceivably improving tolerability. Ongoing work is seeking to understand whether there are changes in upper airway muscle recruitability as well as other change in endotype traits following weight loss surgery.

Pharmacotherapy for OSA

There is a great deal of promise in tailoring pharmacotherapy to individual sleep traits. Acetazolamide, for instance, results in improvements an AHI for both obstructive and central sleep apnea through changes in chemosensitivity and is generally well-tolerated (Schmickl CN, et al. Physiol Rep. 2021;9[20]:e15071). Eszopiclone has been used to raise the arousal threshold for those who awaken from breathing events too easily. With added time, individuals with a low arousal threshold can more effectively recruit upper airway dilator muscles without waking up. Pharmacotherapy to improve upper airway recruitability with combination noradrenergic stimulation and antimuscarinic activity has limited data thus far but may be a useful part of the sleep armamentarium moving forward.

Summary

OSA is a public health priority, and the current global CPAP shortage emphasizes the need for alternative OSA therapies. The ideal therapy for a given patient requires a careful consideration of their individual traits and will be much more refined when endotyping is available in a routine clinical setting. Individualized sleep apnea treatment is the future of sleep medicine and a one-size fits all approach no longer meets the needs of our patients given the current state of sleep medicine knowledge.

Dr. Nokes, Dr. Schmickl, and Dr. Malhotra are with the University of California, San Diego, Division of Pulmonary, Critical Care, and Sleep Medicine, La, Jolla, CA. Dr. Nokes also is with the Veterans Affairs San Diego Healthcare System, sleep section, San Diego, CA. Dr. Vahabzadeh-Hagh is with the University of California, San Diego, Department of Otolaryngology, San Diego, CA.