CHEST
Postgraduate Education Corner CONTEMPORARY REVIEWS IN SLEEP MEDICINE
Novel and Emerging Nonpositive Airway Pressure Therapies for Sleep Apnea John G. Park, MD, FCCP; Timothy M. Morgenthaler, MD, FCCP; and Peter C. Gay, MD, FCCP
CPAP therapy has remained the standard of care for the treatment of sleep apnea for nearly 4 decades. Its overall effectiveness, however, has been limited by incomplete adherence despite many efforts to improve comfort. Conventional alternative therapies include oral appliances and upper airway surgeries. Recently, several innovative alternatives to CPAP have been developed. These novel approaches include means to increase arousal thresholds, electrical nerve stimulation, oral vacuum devices, and nasal expiratory resistive devices. We will review the physiologic mechanisms and the current evidence for these novel treatments. CHEST 2013; 144 (6):1946–1952 Abbreviations: AHI 5 apnea-hypopnea index; CAI 5 central apnea index; CHF 5 congestive heart failure; CSA 5 central sleep apnea; EPAP 5 nasal expiratory positive airway pressure; HGNS 5 hypoglossal nerve stimulator; OAI 5 obstructive apnea index; OPT 5 oral pressure therapy; PNS 5 phrenic nerve stimulation; REM 5 rapid eye movement
a disorder characterized by repetitive airOSAwayiscollapses during sleep. Frequent obstructions
result in increased arousal frequency and surges in sympathetic activity that correlate with increased cardiovascular morbidity and mortality.1-5 The most consistently effective therapy involves the use of a CPAP device that splints the airway open to maintain patency.6 While this is very efficacious, adherence with CPAP remains suboptimal.7 Studies concentrating on improving longterm adherence have achieved 1-year adherence rates as high as 81%, but rates in more current studies range from 35% to 81%.8-12 Although not inferior to adherence noted in many pharmacologic therapies, other treatment options have emerged in efforts to address this issue. The role of upper airway surgery and the use of an oral appliance in the treatment of OSA have been extensively reviewed previously.13,14 Although these treatment options provide alternatives to CPAP, they are not without limitations. In this review, we Manuscript received February 4, 2013; revision accepted April 22, 2013. Affiliations: From the Mayo Clinic College of Medicine, Rochester, MN. Correspondence to: John G. Park, MD, FCCP, 200 First Ave SW, Gonda 17W, Rochester, MN 55905; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-0273 1946
will look at novel non-CPAP forms of therapy for sleep apnea. Nasal Expiratory Positive Airway Pressure Device Morrell et al,15 using a fiber-optic endoscope, measured the cross-sectional area of the retropalatal region in humans during sleep. They concluded that the endexpiratory cross-sectional area progressively decreased in breaths leading up to an apnea. This led Colrain et al16 to test a novel nasal expiratory positive airway pressure (EPAP) device (not to be confused with the expiratory positive airway pressure setting on bilevel ventilation devices) on 24 subjects with OSA and six subjects with primary snoring. This unidirectional flow-resistance device, regulating flow through the nostrils, creates expiratory flow resistance ⱕ 90 cm H2O/L/s without any inspiratory resistance. Its effectiveness was confirmed as the apnea-hypopnea index (AHI) deceased from 24.8 ⫾ 22 to 14.2 ⫾ 22 (P , .001). In particular, among 12 subjects with mild OSA, the mean AHI essentially normalized (10 ⫾ 4 to 4 ⫾ 3). In those with moderate (n 5 8) and severe (n 5 7) OSA, the mean AHI dropped from 19 to 8 and 59 to 40, respectively. Two subjects with AHI . 70, however, did not have any treatment effect.16 Postgraduate Education Corner
After modification of the device to the current EPAP device (Provent; Ventus Medical Inc) (Fig 1),17 Rosenthal et al18 conducted a three-center study of 34 subjects using three different expiratory resistance devices (50, 80, and 110 cm H2O/L/s; the current marketed device has resistance close to 50 cm H2O/L/s) with follow-up polysomnography after 30 days. Among 28 subjects who completed the protocol, the mean AHI decreased from 24.5 ⫾ 23.6 on the diagnostic study to 13.5 ⫾ 18.7 on the initial treatment nights (P , .001). After 30 days, the AHI remained at 15.5 ⫾ 18.9 (P , .001, compared with control night) with 94% of participants reporting subjective adherence of allnight use. At 30-day follow-up, 41% had at least a 50% reduction in their AHI compared with the initial polysomnography. Interestingly, no statistical difference in the residual AHI was noted among the three different expiratory resistance settings. Subsequently, a prospective, sham-controlled, randomized, double-blinded trial was conducted at 19 centers across the United States. After screening 5,688 subjects, 250 subjects were randomized to an EPAP device vs a sham device. Due to various issues, including noncompliance and inability to tolerate the device, 144 subjects completed a 3-month trial.17 Of 31 exclusion criteria, notable items included persistent nasal blockage in one or both nostrils, severe nocturnal desaturations, history of frequent or poorly treated nasal allergies or sinusitis, or use of any sedating medications. Mouth breathing was not used as an exclusion criterion. Most of the subjects had mild OSA; the baseline AHI in the EPAP device group was 13.8, and the sham group was 11.1. The use of the EPAP device resulted in a mean AHI reduction of 52.7%. Even in those with severe OSA (17 subjects with AHI . 30), there was a median reduction of 39.2%. There was a
small but statistically significant improvement in sleepiness as measured by the Epworth Sleepiness Scale (from 9.9 to 7.2 in the treatment group vs 9.6 to 8.3 in the sham group). Dry mouth, discomfort with the device, and difficulty exhaling were among the most common reasons for discontinuing use. In an attempt to understand the physiologic mechanism of the EPAP device, Braga et al19 used MRI to compare the changes in lung volumes and upper airway diameter in awake subjects while the subjects were wearing the EPAP device. The investigators also measured the changes in Pco2 before and after using the device. Their finding, in a small study of 10 subjects, suggests the EPAP device produces lung hyperinflation that causes tracheal traction. This force, in turn, may be transmitted to the upper airway, possibly decreasing its collapsibility. There are some significant limitations regarding our knowledge of EPAP device efficacy. In the Rosenthal et al18 study, 15% of patients did not accept the treatment after enrollment or were withdrawn due to ineffectiveness. The authors did not find a significant treatment effect on sleep architecture. In this study, only subjective adherence was reported. Using 50% reduction in AHI and final AHI , 10 as criteria for success, only 14 of 28 subjects (50%) achieved that outcome at initial therapy and 11 of 28 (39%) at 1 month. In a follow-up to the second study evaluating EPAP device efficacy over 12 months, 10 of 51 initial eligible patients chose not to continue with the devices for varied reasons, but in those who continued its use, reductions in AHI seen at baseline persisted over the 12 months.20 Subjectively reported adherence was 89% of nights. Objective assessments of sleepiness, hypertension, and other cardiovascular outcomes have yet to be reported. Overall, it appears that the EPAP device may be an alternative deserving of a trial for those with mild OSA or those who are intolerant of CPAP therapy. Based on published data, however, severe nocturnal desaturations (defined as saturation , 75% for . 25% of the first 4 h or 10% of the entire diagnostic study) and persistent nasal blockage should be considered contraindications. If used, testing is required to assess effectiveness of therapy. To perform testing, a special nasal pressure transducer is available from the manufacturer that will connect in a similar manner as other nasal pressure transducers. Further study is needed to anticipate which patients will tolerate the EPAP device with an assessment of objective adherence. Electrical Stimulation
Figure 1. Nasal expiratory positive airway pressure (EPAP) device. (Reprinted with permission from Berry et al.17) journal.publications.chestnet.org
Remmers et al,21 in 1978, using a series of esophageal and pharyngeal pressure recordings, concluded that the upper airway occlusion in OSA occurred at the CHEST / 144 / 6 / DECEMBER 2013
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level of the genioglossus. A subsequent study showed that stimulation of the ceratohyoid muscles restored airway patency in an experimental model of increased airway resistance.22 Based on these reports, Miki et al23 evaluated a percutaneous genioglossus stimulator for OSA. On six subjects, the researchers placed, at the submental region, two electrodes that would be triggered by a decrease in tracheal breath sounds. In this group, the AHI decreased from 39.2 to 11.7 without an apparent increase in arousals, although the actual arousal index was not reported. Stage N1 and N2 sleep decreased with an increase in N3 sleep, also suggesting an improved sleep without significant interruptions from the submental stimulator. Unfortunately, when submental stimulation was administered intermittently without an event association, there was no change in AHI or sleep architecture.24 An attempt at using both submental and intraoral stimulation given at a different phase of respiration could not abort a respiratory event without causing an arousal.25 Due to activation of several groups of muscles via the transcutaneous approach, Eisele et al26 approached direct activation of genioglossus by stimulating the hypoglossal nerve. They found that stimulation of either the main trunk or the distal hypoglossal nerve during sleep resulted in upper airway opening without causing arousals. This group then integrated an implantable intrathoracic pressure sensor to predict the onset of inspiration. (Fig 2).27 This integration would time the hypoglossal nerve stimulation to coincide with inspiratory effort to open the upper airway during sleep
Figure 2. Hypoglossal nerve stimulator. This is one (Inspire II; Inspire Medical Systems Inc) of several models currently being tested. (Reprinted with permission from Van de Heyning et al.27) 1948
(Fig 3).28 They tested one such device, Inspire I (Inspire Medical Systems Inc), on eight subjects and found that non-rapid eye movement AHI decreased from 52.0 ⫾ 20.4 to 22.6 ⫾ 12.1 and rapid eye movement (REM) AHI decreased from 48.2 ⫾ 30.5 to 16.6 ⫾ 17.1 (full-night AHI was not reported).29 Reduction in AHI was accomplished with nonstatistically significant increases in N3 and REM sleep, and improved sleep efficiency. Arousal index was not reported. Higher stimulus amplitude and frequency were needed to maintain efficacy at 3- and 6-month follow-up periods. No tongue abrasions were noted throughout the study period, but they did note some device malfunctions, including pulse generator failure, transient asynchronous stimulation, and electrode breakage. More recently, a multicenter study involving 21 patients was reported in which a different hypoglossal nerve stimulator (HGNS) (Apnex Medical Inc) was used.28 The difference between the Inspire device and Apnex Medical device is that the respiratory sensing leads in the Apnex Medical HGNS measure the thoracic bioimpedance, which is tunneled subcutaneously to the costal margins on either side of the sternum. Interestingly, their inclusion criteria were moderate to severe sleep apnea (AHI . 20) with predominance of hypopnea (ⱖ 80% of all events). At 3 months, AHI decreased by 56% (from 43 to 19), with decreases in total and respiratory-related arousals (47% and 66%, respectively). Sleep architecture improved with reduced stage N1 and increased REM sleep. All measured parameters of symptoms (Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, Sleep Apnea Quality of Life Index, Pittsburg Sleep Quality Index, and Beck Depression Inventory) improved. Notably, these improvements were maintained at 6 months. However, at least one adverse event was reported in 71% of the patients, with numbness/pain at the insertion site and tongue abrasion (due to constant movement of the tongue over the incisors) being the most common events. In their post hoc analysis, BMI ⱖ 35 kg/m2 seem to be an indicator of poor response. In a subsequent study, Schwartz et al30 showed that maximal inspiratory airflow nearly doubled from 215 mL/s to 509 mL/s during maximal stimulation, without any resultant arousals. The net effect of HGNS was to abolish airflow limitation in 17 patients with OSA and to markedly improve limited airflow in the remaining 13 patients tested. Inspiratory airflow returned to baseline when the stimulator was turned off, consistent with the effect being directly related to hypoglossal nerve activation rather than arousals. Van de Heyning et al27 identified factors that would increase the likelihood of success by HGNS. These factors were BMI ⱕ 32 kg/m2, AHI ⱕ 50, and lack of concentric palatal collapse noted during drug-induced Postgraduate Education Corner
Figure 3. Effect of hypoglossal nerve stimulation (Apnex Medical Inc device) in opening of the retropalatal region. (Reprinted with permission from Eastwood et al.28)
sleep endoscopy (using either midazolam or propofol). In a prospective validation study of these indices, seven of eight subjects meeting these criteria responded (as defined by a 50% reduction in the AHI with a resultant AHI , 20). The mean AHI dropped from 38.9 to 10 at 6 months. As this group did not select those with predominant hypopneas, the apnea index among those with favorable parameters dropped from 22.7 to 6.4. Serious adverse events reported included infections (two subjects) while nonserious events included pain, stiffness, sore throat, fever, and local swelling. Due to concerns of nerve damage with constant hypoglossal-nerve stimulation, Mann et al31 approached this problem by directly stimulating the genioglossus muscle, using a percutaneously placed, bipolar hooked wire in healthy adults. They reported a 33% to 284% increase in the hypopharyngeal airway diameter with genioglossus muscle stimulation in 79% of their test subjects. Unfortunately, subsequent reports on this topic were not found. While not yet approved for clinical use, HGNS holds promise in the treatment of OSA. It improves adherence while having some efficacy, even in patients with moderate to severe OSA (AHI ⱕ 50), especially if their BMI is ⱕ 32 kg/m2. Long-term studies suggest, however, that the stimulus parameter requires adjustment in 3 to 6 months after implantation. The frequencies with which it will need to be adjusted thereafter remain unclear. Oral Pressure Therapy Rather than applying positive pressure to the upper airways, a novel device that applies gentle oral suction sufficient to anteriorly and superiorly displace the soft palate and the tongue has been developed. Malhotra et al32 studied the efficacy of this oral pressure journal.publications.chestnet.org
therapy (OPT) device, known as Winx (ApniCure, Inc) (Fig 4). While their results have only been published in abstract form, they showed that mean AHI among 30 subjects decreased from 31.8 to 19.7, with further reduction to 17.1 after 28 days of use. However, during their poster presentation, they suggested that the AHI had actually decreased in 60 subjects from 31 to 14.7 (A. Malholtra, MD, oral communication, May 2012). When success was defined as at least a 50% reduction in AHI and AHI , 20, 25 of the 60 subjects responded. In this group of responders, AHI decreased from 28 to 5.3. Even among those with severe OSA, AHI decreased from 45.6 to 9.1. Unfortunately, they did not provide any subject characteristics that predicted success. However, in this cohort of 60 subjects, median nightly use was 6 h, with use . 4 h on 87.5% of nights. Subsequently, Schwab et al33 attempted to delineate the mechanism by which the OPT device worked. Their work was also published in abstract form.33 They proceeded with MRI imaging, which revealed a 75.4% increase in average retropalatal airway space due to 12.4-mm anterior and 9.9-mm superior displacement of the soft palate and 7.7-mm anterior displacement of the anterior tongue. While these results are very preliminary and we need to wait for the published manuscript to better scrutinize them, the use of an OPT may offer a novel and viable alternative to CPAP in treatment of OSA, even among those with severe OSA. Lack of universal response, however, may be due to insufficient enlargement of the retropalatal space or collapse of the airway at a different site. Further work will be required to better delineate its applicability. Arousal Threshold Therapy There are emerging data that suggest arousals from sleep may contribute to the severity of OSA. CHEST / 144 / 6 / DECEMBER 2013
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Eckert et al38 hypothesized that if the arousal threshold was raised pharmacologically, causing more sleep-stage stability, there would be adequate time for respiratory muscle recruitment to stabilize the upper airway and reduce the AHI. Using eszopiclone in 17 OSA subjects, this theory was then tested in a double-blind, placebocontrolled, randomized, cross-over study.38 They showed that the use of eszopiclone reduced AHI by 23% (exclusively during non-REM sleep) and increased arousal threshold by 18% during N2 sleep. Noting that their subjects had different arousal thresholds, the researchers reported that eszopiclone had the greatest effect on those who had low arousal threshold at baseline, as it reduced AHI by 43% in this subgroup. While these results are encouraging and warrant further investigation, a previous study from Rosenberg et al39 did not show such improvements in AHI with the use of eszopiclone. Phrenic Nerve Stimulation for Central Sleep Apnea
Figure 4. A, Winx device, an oral pressure device that uses gentle suction to anteriorly and superiorly displace the tongue and the soft palate. B, Effect of oral pressure device on the tongue and soft palate displacement.
Younes et al34,35 showed that arousals destabilize the ventilatory response to stimuli such as apneas, which may promote an increased frequency of respiratory events. Ratnavadivel et al36 have shown that AHI may decrease by 50% in N3 sleep relative to stage N2 sleep where the arousal threshold is much lower. Jordan et al37 also showed that genioglossus muscle tone was higher in N3 compared with N2 sleep, and hypothesized that if patients were able to avoid arousals during respiratory instability, inherent chemoreceptor activity will lead to airway dilation and avoid a respiratory event. 1950
Central sleep apnea (CSA) poses a different set of problems in that the mechanism of apnea occurs due to problems with the central respiratory controller and not because of upper airway collapse. It is estimated that up to 40% of patients with left ventricular ejection fraction , 45% will have CSA.40,41 Unfortunately, CSA superimposed on congestive heart failure (CHF) is associated with worsening quality of life and higher morbidity.42,43 While CPAP has shown some success in treating this breathing disorder, a large, multicenter trial (the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure trial) failed to show improvements in the primary end point of mortality or cardiac transplant, although some secondary parameters such as quality of life, nocturnal oxygen saturation, ejection fraction, and 6-min walk were improved.44 Two randomized trials are underway that use a more advanced positive airway pressure device (eg, adaptive servoventilation) to assess its impact on the outcomes of those patients with CSA and CHF. Within this year, however, two publications looked at a novel method of transvascular phrenic nerve stimulation (PNS) to treat CSA.45,46 The use of PNS in augmenting respiration, however, is not new. Since one of the first publications, in 1948 by Sarnoff et al,47 PNS has been used in patients with ventilator failure due to either congenital abnormalities or traumatic neurologic insults. Its application in those with CSA, however, is novel and the two groups of investigators have shown that it is feasible to mitigate CSA, at least temporarily, with PNS. Ponikowski et al45 investigated PNS in 16 subjects with an average ejection fraction of 30% and AHI of 45 (central apnea index [CAI], 27; obstructive apnea Postgraduate Education Corner
index [OAI], 1; hypopnea index, 10). The transvenous nerve stimulators were placed via the axillary or subclavian vein into the right brachiocephalic vein, the left brachiocephalic vein, or the left pericardiophrenic vein. With the activation of PNS, AHI decreased to 23 with near resolution of CAI (1 vs 27; P , .001), OAI trended negatively (1 to 4; P 5 .56), and the hypopnea index remained unchanged. This was accomplished without a significant change in sleep efficiency and a . 50% reduction in the arousal index. Similarly, Zhang et al46 implanted 16 patients with PNS in similar positions and found that AHI decreased from 33.8 (where majority of the sleep-related breathing disorder events were CAI) to 8.1. They also showed a nearly 66% reduction in arousal index while the PNS was activated. Both groups experienced several problems. Technical difficulties in placement of the catheters were noted. Ponikowski’s group initially enrolled 31 subjects but was only able to proceed with 16 due to placement and capture issues. Likewise, Zhang’s group could not analyze three subjects due to the inability of the catheter to stimulate the phrenic nerve. Since these catheters are placed transvascularly, the position of the tip is not constant and may migrate away from the vascular wall, resulting in ineffective stimulus of the phrenic nerve. After 2 days of catheter placement, one patient in the Ponikowski’s group developed a thrombus at the catheter tip. This complication was not reported from Zhang’s group, as the catheter in their study was removed after 1 day. The number of obstructive events increased, although this was not statistically significant, in the Ponikowski et al45 study. This was not reported in the Zhang et al46 study, as their subjects had nearly exclusively central apnea with a mean OAI of only 0.7. This phenomenon of potentially increasing obstructive events has been well described in previous reports48 and may be related to decreasing the critical airway closing pressure by stimulating the diaphragm while the upper airway remains relaxed and unstimulated. As these two trials are pilot and feasibility studies, long-term complications such as arrhythmias and potential interactions with other implanted devices remain unclear. Furthermore, the impact of reducing CSA via PNS with respect to long-term outcomes such as mortality and morbidity has yet to be determined. Regardless, PNS, perhaps by a more direct route, as with hypoglossal nerve stimulation, may potentially offer a viable alternative to positive airway pressure devices in the treatment of CSA in those with CHF. In conclusion, innovative devices are being actively developed to treat sleep apnea. While CPAP remains the most consistently efficacious, albeit with adherence issues, it is encouraging to note that other treatment options are emerging. Of the devices discussed, journal.publications.chestnet.org
the nasal EPAP device and OPT are currently approved for clinical use, with the EPAP device being only for those with mild OSA. Thus far, data suggest that HGNS may also benefit some patients with moderate to severe OSA and arousal threshold therapy will require further investigation. These technological advancements are exciting and encouraging to those who may be struggling with CPAP. With continued innovation in this field, we can hope to offer various treatment options as part of a comprehensive chronic care model to effectively treat sleep apnea and mitigate its untoward consequences. Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
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Postgraduate Education Corner
Postgraduate Education Corner CONTEMPORARY REVIEWS IN SLEEP MEDICINE
Novel and Emerging Nonpositive Airway Pressure Therapies for Sleep Apnea John G. Park, MD, FCCP; Timothy M. Morgenthaler, MD, FCCP; and Peter C. Gay, MD, FCCP
CPAP therapy has remained the standard of care for the treatment of sleep apnea for nearly 4 decades. Its overall effectiveness, however, has been limited by incomplete adherence despite many efforts to improve comfort. Conventional alternative therapies include oral appliances and upper airway surgeries. Recently, several innovative alternatives to CPAP have been developed. These novel approaches include means to increase arousal thresholds, electrical nerve stimulation, oral vacuum devices, and nasal expiratory resistive devices. We will review the physiologic mechanisms and the current evidence for these novel treatments. CHEST 2013; 144 (6):1946–1952 Abbreviations: AHI 5 apnea-hypopnea index; CAI 5 central apnea index; CHF 5 congestive heart failure; CSA 5 central sleep apnea; EPAP 5 nasal expiratory positive airway pressure; HGNS 5 hypoglossal nerve stimulator; OAI 5 obstructive apnea index; OPT 5 oral pressure therapy; PNS 5 phrenic nerve stimulation; REM 5 rapid eye movement
a disorder characterized by repetitive airOSAwayiscollapses during sleep. Frequent obstructions
result in increased arousal frequency and surges in sympathetic activity that correlate with increased cardiovascular morbidity and mortality.1-5 The most consistently effective therapy involves the use of a CPAP device that splints the airway open to maintain patency.6 While this is very efficacious, adherence with CPAP remains suboptimal.7 Studies concentrating on improving longterm adherence have achieved 1-year adherence rates as high as 81%, but rates in more current studies range from 35% to 81%.8-12 Although not inferior to adherence noted in many pharmacologic therapies, other treatment options have emerged in efforts to address this issue. The role of upper airway surgery and the use of an oral appliance in the treatment of OSA have been extensively reviewed previously.13,14 Although these treatment options provide alternatives to CPAP, they are not without limitations. In this review, we Manuscript received February 4, 2013; revision accepted April 22, 2013. Affiliations: From the Mayo Clinic College of Medicine, Rochester, MN. Correspondence to: John G. Park, MD, FCCP, 200 First Ave SW, Gonda 17W, Rochester, MN 55905; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-0273 1946
will look at novel non-CPAP forms of therapy for sleep apnea. Nasal Expiratory Positive Airway Pressure Device Morrell et al,15 using a fiber-optic endoscope, measured the cross-sectional area of the retropalatal region in humans during sleep. They concluded that the endexpiratory cross-sectional area progressively decreased in breaths leading up to an apnea. This led Colrain et al16 to test a novel nasal expiratory positive airway pressure (EPAP) device (not to be confused with the expiratory positive airway pressure setting on bilevel ventilation devices) on 24 subjects with OSA and six subjects with primary snoring. This unidirectional flow-resistance device, regulating flow through the nostrils, creates expiratory flow resistance ⱕ 90 cm H2O/L/s without any inspiratory resistance. Its effectiveness was confirmed as the apnea-hypopnea index (AHI) deceased from 24.8 ⫾ 22 to 14.2 ⫾ 22 (P , .001). In particular, among 12 subjects with mild OSA, the mean AHI essentially normalized (10 ⫾ 4 to 4 ⫾ 3). In those with moderate (n 5 8) and severe (n 5 7) OSA, the mean AHI dropped from 19 to 8 and 59 to 40, respectively. Two subjects with AHI . 70, however, did not have any treatment effect.16 Postgraduate Education Corner
After modification of the device to the current EPAP device (Provent; Ventus Medical Inc) (Fig 1),17 Rosenthal et al18 conducted a three-center study of 34 subjects using three different expiratory resistance devices (50, 80, and 110 cm H2O/L/s; the current marketed device has resistance close to 50 cm H2O/L/s) with follow-up polysomnography after 30 days. Among 28 subjects who completed the protocol, the mean AHI decreased from 24.5 ⫾ 23.6 on the diagnostic study to 13.5 ⫾ 18.7 on the initial treatment nights (P , .001). After 30 days, the AHI remained at 15.5 ⫾ 18.9 (P , .001, compared with control night) with 94% of participants reporting subjective adherence of allnight use. At 30-day follow-up, 41% had at least a 50% reduction in their AHI compared with the initial polysomnography. Interestingly, no statistical difference in the residual AHI was noted among the three different expiratory resistance settings. Subsequently, a prospective, sham-controlled, randomized, double-blinded trial was conducted at 19 centers across the United States. After screening 5,688 subjects, 250 subjects were randomized to an EPAP device vs a sham device. Due to various issues, including noncompliance and inability to tolerate the device, 144 subjects completed a 3-month trial.17 Of 31 exclusion criteria, notable items included persistent nasal blockage in one or both nostrils, severe nocturnal desaturations, history of frequent or poorly treated nasal allergies or sinusitis, or use of any sedating medications. Mouth breathing was not used as an exclusion criterion. Most of the subjects had mild OSA; the baseline AHI in the EPAP device group was 13.8, and the sham group was 11.1. The use of the EPAP device resulted in a mean AHI reduction of 52.7%. Even in those with severe OSA (17 subjects with AHI . 30), there was a median reduction of 39.2%. There was a
small but statistically significant improvement in sleepiness as measured by the Epworth Sleepiness Scale (from 9.9 to 7.2 in the treatment group vs 9.6 to 8.3 in the sham group). Dry mouth, discomfort with the device, and difficulty exhaling were among the most common reasons for discontinuing use. In an attempt to understand the physiologic mechanism of the EPAP device, Braga et al19 used MRI to compare the changes in lung volumes and upper airway diameter in awake subjects while the subjects were wearing the EPAP device. The investigators also measured the changes in Pco2 before and after using the device. Their finding, in a small study of 10 subjects, suggests the EPAP device produces lung hyperinflation that causes tracheal traction. This force, in turn, may be transmitted to the upper airway, possibly decreasing its collapsibility. There are some significant limitations regarding our knowledge of EPAP device efficacy. In the Rosenthal et al18 study, 15% of patients did not accept the treatment after enrollment or were withdrawn due to ineffectiveness. The authors did not find a significant treatment effect on sleep architecture. In this study, only subjective adherence was reported. Using 50% reduction in AHI and final AHI , 10 as criteria for success, only 14 of 28 subjects (50%) achieved that outcome at initial therapy and 11 of 28 (39%) at 1 month. In a follow-up to the second study evaluating EPAP device efficacy over 12 months, 10 of 51 initial eligible patients chose not to continue with the devices for varied reasons, but in those who continued its use, reductions in AHI seen at baseline persisted over the 12 months.20 Subjectively reported adherence was 89% of nights. Objective assessments of sleepiness, hypertension, and other cardiovascular outcomes have yet to be reported. Overall, it appears that the EPAP device may be an alternative deserving of a trial for those with mild OSA or those who are intolerant of CPAP therapy. Based on published data, however, severe nocturnal desaturations (defined as saturation , 75% for . 25% of the first 4 h or 10% of the entire diagnostic study) and persistent nasal blockage should be considered contraindications. If used, testing is required to assess effectiveness of therapy. To perform testing, a special nasal pressure transducer is available from the manufacturer that will connect in a similar manner as other nasal pressure transducers. Further study is needed to anticipate which patients will tolerate the EPAP device with an assessment of objective adherence. Electrical Stimulation
Figure 1. Nasal expiratory positive airway pressure (EPAP) device. (Reprinted with permission from Berry et al.17) journal.publications.chestnet.org
Remmers et al,21 in 1978, using a series of esophageal and pharyngeal pressure recordings, concluded that the upper airway occlusion in OSA occurred at the CHEST / 144 / 6 / DECEMBER 2013
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level of the genioglossus. A subsequent study showed that stimulation of the ceratohyoid muscles restored airway patency in an experimental model of increased airway resistance.22 Based on these reports, Miki et al23 evaluated a percutaneous genioglossus stimulator for OSA. On six subjects, the researchers placed, at the submental region, two electrodes that would be triggered by a decrease in tracheal breath sounds. In this group, the AHI decreased from 39.2 to 11.7 without an apparent increase in arousals, although the actual arousal index was not reported. Stage N1 and N2 sleep decreased with an increase in N3 sleep, also suggesting an improved sleep without significant interruptions from the submental stimulator. Unfortunately, when submental stimulation was administered intermittently without an event association, there was no change in AHI or sleep architecture.24 An attempt at using both submental and intraoral stimulation given at a different phase of respiration could not abort a respiratory event without causing an arousal.25 Due to activation of several groups of muscles via the transcutaneous approach, Eisele et al26 approached direct activation of genioglossus by stimulating the hypoglossal nerve. They found that stimulation of either the main trunk or the distal hypoglossal nerve during sleep resulted in upper airway opening without causing arousals. This group then integrated an implantable intrathoracic pressure sensor to predict the onset of inspiration. (Fig 2).27 This integration would time the hypoglossal nerve stimulation to coincide with inspiratory effort to open the upper airway during sleep
Figure 2. Hypoglossal nerve stimulator. This is one (Inspire II; Inspire Medical Systems Inc) of several models currently being tested. (Reprinted with permission from Van de Heyning et al.27) 1948
(Fig 3).28 They tested one such device, Inspire I (Inspire Medical Systems Inc), on eight subjects and found that non-rapid eye movement AHI decreased from 52.0 ⫾ 20.4 to 22.6 ⫾ 12.1 and rapid eye movement (REM) AHI decreased from 48.2 ⫾ 30.5 to 16.6 ⫾ 17.1 (full-night AHI was not reported).29 Reduction in AHI was accomplished with nonstatistically significant increases in N3 and REM sleep, and improved sleep efficiency. Arousal index was not reported. Higher stimulus amplitude and frequency were needed to maintain efficacy at 3- and 6-month follow-up periods. No tongue abrasions were noted throughout the study period, but they did note some device malfunctions, including pulse generator failure, transient asynchronous stimulation, and electrode breakage. More recently, a multicenter study involving 21 patients was reported in which a different hypoglossal nerve stimulator (HGNS) (Apnex Medical Inc) was used.28 The difference between the Inspire device and Apnex Medical device is that the respiratory sensing leads in the Apnex Medical HGNS measure the thoracic bioimpedance, which is tunneled subcutaneously to the costal margins on either side of the sternum. Interestingly, their inclusion criteria were moderate to severe sleep apnea (AHI . 20) with predominance of hypopnea (ⱖ 80% of all events). At 3 months, AHI decreased by 56% (from 43 to 19), with decreases in total and respiratory-related arousals (47% and 66%, respectively). Sleep architecture improved with reduced stage N1 and increased REM sleep. All measured parameters of symptoms (Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, Sleep Apnea Quality of Life Index, Pittsburg Sleep Quality Index, and Beck Depression Inventory) improved. Notably, these improvements were maintained at 6 months. However, at least one adverse event was reported in 71% of the patients, with numbness/pain at the insertion site and tongue abrasion (due to constant movement of the tongue over the incisors) being the most common events. In their post hoc analysis, BMI ⱖ 35 kg/m2 seem to be an indicator of poor response. In a subsequent study, Schwartz et al30 showed that maximal inspiratory airflow nearly doubled from 215 mL/s to 509 mL/s during maximal stimulation, without any resultant arousals. The net effect of HGNS was to abolish airflow limitation in 17 patients with OSA and to markedly improve limited airflow in the remaining 13 patients tested. Inspiratory airflow returned to baseline when the stimulator was turned off, consistent with the effect being directly related to hypoglossal nerve activation rather than arousals. Van de Heyning et al27 identified factors that would increase the likelihood of success by HGNS. These factors were BMI ⱕ 32 kg/m2, AHI ⱕ 50, and lack of concentric palatal collapse noted during drug-induced Postgraduate Education Corner
Figure 3. Effect of hypoglossal nerve stimulation (Apnex Medical Inc device) in opening of the retropalatal region. (Reprinted with permission from Eastwood et al.28)
sleep endoscopy (using either midazolam or propofol). In a prospective validation study of these indices, seven of eight subjects meeting these criteria responded (as defined by a 50% reduction in the AHI with a resultant AHI , 20). The mean AHI dropped from 38.9 to 10 at 6 months. As this group did not select those with predominant hypopneas, the apnea index among those with favorable parameters dropped from 22.7 to 6.4. Serious adverse events reported included infections (two subjects) while nonserious events included pain, stiffness, sore throat, fever, and local swelling. Due to concerns of nerve damage with constant hypoglossal-nerve stimulation, Mann et al31 approached this problem by directly stimulating the genioglossus muscle, using a percutaneously placed, bipolar hooked wire in healthy adults. They reported a 33% to 284% increase in the hypopharyngeal airway diameter with genioglossus muscle stimulation in 79% of their test subjects. Unfortunately, subsequent reports on this topic were not found. While not yet approved for clinical use, HGNS holds promise in the treatment of OSA. It improves adherence while having some efficacy, even in patients with moderate to severe OSA (AHI ⱕ 50), especially if their BMI is ⱕ 32 kg/m2. Long-term studies suggest, however, that the stimulus parameter requires adjustment in 3 to 6 months after implantation. The frequencies with which it will need to be adjusted thereafter remain unclear. Oral Pressure Therapy Rather than applying positive pressure to the upper airways, a novel device that applies gentle oral suction sufficient to anteriorly and superiorly displace the soft palate and the tongue has been developed. Malhotra et al32 studied the efficacy of this oral pressure journal.publications.chestnet.org
therapy (OPT) device, known as Winx (ApniCure, Inc) (Fig 4). While their results have only been published in abstract form, they showed that mean AHI among 30 subjects decreased from 31.8 to 19.7, with further reduction to 17.1 after 28 days of use. However, during their poster presentation, they suggested that the AHI had actually decreased in 60 subjects from 31 to 14.7 (A. Malholtra, MD, oral communication, May 2012). When success was defined as at least a 50% reduction in AHI and AHI , 20, 25 of the 60 subjects responded. In this group of responders, AHI decreased from 28 to 5.3. Even among those with severe OSA, AHI decreased from 45.6 to 9.1. Unfortunately, they did not provide any subject characteristics that predicted success. However, in this cohort of 60 subjects, median nightly use was 6 h, with use . 4 h on 87.5% of nights. Subsequently, Schwab et al33 attempted to delineate the mechanism by which the OPT device worked. Their work was also published in abstract form.33 They proceeded with MRI imaging, which revealed a 75.4% increase in average retropalatal airway space due to 12.4-mm anterior and 9.9-mm superior displacement of the soft palate and 7.7-mm anterior displacement of the anterior tongue. While these results are very preliminary and we need to wait for the published manuscript to better scrutinize them, the use of an OPT may offer a novel and viable alternative to CPAP in treatment of OSA, even among those with severe OSA. Lack of universal response, however, may be due to insufficient enlargement of the retropalatal space or collapse of the airway at a different site. Further work will be required to better delineate its applicability. Arousal Threshold Therapy There are emerging data that suggest arousals from sleep may contribute to the severity of OSA. CHEST / 144 / 6 / DECEMBER 2013
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Eckert et al38 hypothesized that if the arousal threshold was raised pharmacologically, causing more sleep-stage stability, there would be adequate time for respiratory muscle recruitment to stabilize the upper airway and reduce the AHI. Using eszopiclone in 17 OSA subjects, this theory was then tested in a double-blind, placebocontrolled, randomized, cross-over study.38 They showed that the use of eszopiclone reduced AHI by 23% (exclusively during non-REM sleep) and increased arousal threshold by 18% during N2 sleep. Noting that their subjects had different arousal thresholds, the researchers reported that eszopiclone had the greatest effect on those who had low arousal threshold at baseline, as it reduced AHI by 43% in this subgroup. While these results are encouraging and warrant further investigation, a previous study from Rosenberg et al39 did not show such improvements in AHI with the use of eszopiclone. Phrenic Nerve Stimulation for Central Sleep Apnea
Figure 4. A, Winx device, an oral pressure device that uses gentle suction to anteriorly and superiorly displace the tongue and the soft palate. B, Effect of oral pressure device on the tongue and soft palate displacement.
Younes et al34,35 showed that arousals destabilize the ventilatory response to stimuli such as apneas, which may promote an increased frequency of respiratory events. Ratnavadivel et al36 have shown that AHI may decrease by 50% in N3 sleep relative to stage N2 sleep where the arousal threshold is much lower. Jordan et al37 also showed that genioglossus muscle tone was higher in N3 compared with N2 sleep, and hypothesized that if patients were able to avoid arousals during respiratory instability, inherent chemoreceptor activity will lead to airway dilation and avoid a respiratory event. 1950
Central sleep apnea (CSA) poses a different set of problems in that the mechanism of apnea occurs due to problems with the central respiratory controller and not because of upper airway collapse. It is estimated that up to 40% of patients with left ventricular ejection fraction , 45% will have CSA.40,41 Unfortunately, CSA superimposed on congestive heart failure (CHF) is associated with worsening quality of life and higher morbidity.42,43 While CPAP has shown some success in treating this breathing disorder, a large, multicenter trial (the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure trial) failed to show improvements in the primary end point of mortality or cardiac transplant, although some secondary parameters such as quality of life, nocturnal oxygen saturation, ejection fraction, and 6-min walk were improved.44 Two randomized trials are underway that use a more advanced positive airway pressure device (eg, adaptive servoventilation) to assess its impact on the outcomes of those patients with CSA and CHF. Within this year, however, two publications looked at a novel method of transvascular phrenic nerve stimulation (PNS) to treat CSA.45,46 The use of PNS in augmenting respiration, however, is not new. Since one of the first publications, in 1948 by Sarnoff et al,47 PNS has been used in patients with ventilator failure due to either congenital abnormalities or traumatic neurologic insults. Its application in those with CSA, however, is novel and the two groups of investigators have shown that it is feasible to mitigate CSA, at least temporarily, with PNS. Ponikowski et al45 investigated PNS in 16 subjects with an average ejection fraction of 30% and AHI of 45 (central apnea index [CAI], 27; obstructive apnea Postgraduate Education Corner
index [OAI], 1; hypopnea index, 10). The transvenous nerve stimulators were placed via the axillary or subclavian vein into the right brachiocephalic vein, the left brachiocephalic vein, or the left pericardiophrenic vein. With the activation of PNS, AHI decreased to 23 with near resolution of CAI (1 vs 27; P , .001), OAI trended negatively (1 to 4; P 5 .56), and the hypopnea index remained unchanged. This was accomplished without a significant change in sleep efficiency and a . 50% reduction in the arousal index. Similarly, Zhang et al46 implanted 16 patients with PNS in similar positions and found that AHI decreased from 33.8 (where majority of the sleep-related breathing disorder events were CAI) to 8.1. They also showed a nearly 66% reduction in arousal index while the PNS was activated. Both groups experienced several problems. Technical difficulties in placement of the catheters were noted. Ponikowski’s group initially enrolled 31 subjects but was only able to proceed with 16 due to placement and capture issues. Likewise, Zhang’s group could not analyze three subjects due to the inability of the catheter to stimulate the phrenic nerve. Since these catheters are placed transvascularly, the position of the tip is not constant and may migrate away from the vascular wall, resulting in ineffective stimulus of the phrenic nerve. After 2 days of catheter placement, one patient in the Ponikowski’s group developed a thrombus at the catheter tip. This complication was not reported from Zhang’s group, as the catheter in their study was removed after 1 day. The number of obstructive events increased, although this was not statistically significant, in the Ponikowski et al45 study. This was not reported in the Zhang et al46 study, as their subjects had nearly exclusively central apnea with a mean OAI of only 0.7. This phenomenon of potentially increasing obstructive events has been well described in previous reports48 and may be related to decreasing the critical airway closing pressure by stimulating the diaphragm while the upper airway remains relaxed and unstimulated. As these two trials are pilot and feasibility studies, long-term complications such as arrhythmias and potential interactions with other implanted devices remain unclear. Furthermore, the impact of reducing CSA via PNS with respect to long-term outcomes such as mortality and morbidity has yet to be determined. Regardless, PNS, perhaps by a more direct route, as with hypoglossal nerve stimulation, may potentially offer a viable alternative to positive airway pressure devices in the treatment of CSA in those with CHF. In conclusion, innovative devices are being actively developed to treat sleep apnea. While CPAP remains the most consistently efficacious, albeit with adherence issues, it is encouraging to note that other treatment options are emerging. Of the devices discussed, journal.publications.chestnet.org
the nasal EPAP device and OPT are currently approved for clinical use, with the EPAP device being only for those with mild OSA. Thus far, data suggest that HGNS may also benefit some patients with moderate to severe OSA and arousal threshold therapy will require further investigation. These technological advancements are exciting and encouraging to those who may be struggling with CPAP. With continued innovation in this field, we can hope to offer various treatment options as part of a comprehensive chronic care model to effectively treat sleep apnea and mitigate its untoward consequences. Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
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Postgraduate Education Corner
