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Beyond CPAP: Looking to alternative treatments for obstructive sleep apnea
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).
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).
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).
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.