Nerve Stimulation for the Treatment of Obstructive Sleep Apnea

Abstract

Purpose:

This review will trace the elements of neurostimulation for obstructive sleep apnea and details on its implementation, efficacy and safety, immediate clinical outcomes, and future prospects.

Methods:

The literature on upper airway neurostimulation was surveyed from July, 2013, to July 2019, with a focus on the components of devices, evidence for clinical utility, and adverse events.

Results:

Current technology is focused on the hypoglossal nerve stimulation (HNS). The most long-term experience is with the Inspire Medical System (Maple Grove, MN USA) which has both FDA and European regulatory approval. Given the inclusion criteria (BMI <35, ideally <32), AHI 15–65/h, and a favorable anterior-posterior velopharyngeal collapse pattern on DISE), across many centers ~65% of patients who are intolerant to primary therapy achieve clinical success (AHI <20/h with a reduction of <50% in AHI), and more have symptomatic relief. Adverse events are generally mild, often self-limited, with occasional need for uncomplicated surgical adjustments or replacement of the implantable generator. Three other devices are in various phases of development, each with a differences in nerve electrodes, implantable components, power sources, proprietary programming, and activation patterns.

Conclusions.

HNS is not considered a first-line treatment option. HNS therapy, however, should be considered as one alternative therapeutic option for patients meeting the inclusion criteria when more traditional therapeutic options have been considered.

Introduction

Therapies for moderate-to-severe obstructive sleep apnea syndrome (OSA) began in the 1960’s in Europe with the observation that tracheostomy could treat the syndrome of excessive hypersomnolence and pulmonary hypertension, which by the late 1970’s was identified as obstructive sleep apnea syndrome in the United States ¹. OSA becam a major driver of the field of sleep medicine ². By the mid 1980’s mechanisms leading to initiation of apneas and the purposes for mechanical/surgical therapy were understood ³. Interventions now include continuous positive airway pressure (CPAP), oral mandibular advancement devices, anatomic surgery to the upper airway structures, and bariatric surgery ⁴. CPAP is the most common first approach and improvements in quality of life, symptoms of disturbed sleep, and a lower blood pressure accrue with hours of use. It appears that mortality and stroke may be reduced ⁵. However, two years later up to 60% are unable to use or tolerate CPAP therapy ^{6, 7}. Surgical management to address OSA, while effective in some, are not as predictably efficacious nor durable as one would like ⁸. For instance, uvulopalatopharyngoplasty (UPPP) will reduce severe AHI by an average of 30–50%, but residual AHI remains in the mild-to-moderate range (<20/hr) after two years ⁹.

The purpose of this review is to introduce the supporting knowledge for upper airway neurostimulation as a therapy for OSA. The concept of neurostimulation is not new ³ but the approval for hypoglossal nerve stimulation (HNS) use is. HNS will be defined as electrical stimulation of CNXII to activate muscles to open the oropharynx and nasopharynx without creating a positive intraluminal pressure (CPAP), protruding the mandible (oral appliance), or manipulation of the soft tissues or bony structures of the head and neck (anatomic surgery) ¹⁰. The success of HNS is to not only prevent tongue prolapse into the oropharynx, but also to maintain or enlarge the velopharynx keeping the upper airway patent during sleep; it does not however break an apnea . Now 5–7 years after USA and European approvals for use ³, there is a body of literature of published work and commentary on current and future use hypoglossal nerve stimulation (HNS). In the past 3 years there are ~90 publications on HNS. This review is not exhaustive but provides guidance to the literature and an orientation to its implementation in clinical practice.

Eligibility Assessments and Considerations

HNS is generally regarded as a secondary therapy choice for those with moderate to severe OSA in whom CPAP is unsuccessful for one reason or another, or less often primary therapy when CPAP is impractical (e.g. facial disfigurement) or contraindicated (bullous disease or chronic pneumothorax). Before incorporating HNS into a practice, the managing doctors should have understanding of deployment of the primary treatment options for OSA (CPAP, oral devices, and anatomic surgery) and an ability to compare and contrast deployment of HNS to these other options ¹¹. The mechanisms for the success of primary therapy depends upon its success in increasing the size and stiffness of the upper airway collapsible segment, i.e. the nasopharynx, oro-pharynx or less likely the hypopharynx, permitting uninterrupted sleep ^{12, 13}.

At the present time HNS is performed at self-selected centers with advanced cooperation among both surgery and medicine specialists, as it is second line therapy and patient selection is a key component. HNS therapy at present is offered to those who in recent times cannot or do not use CPAP or oral appliances, or who have failed anatomic surgery, often several attempts ¹⁴. Assessments for implant include recognition of medical, psychiatric, neurologic and sleep co-morbidities, some of which might influence a decision for surgery or affect management. Because the technology for CPAP and oral appliance therapies has improved with better knowledge of how to address adherence and efficacy, an ability to assess an “adequate” attempt to use primary therapy is crucial. In the United States, OSA patients are often referred back to sleep medicine for assessments of HNS many years after trying and stopping therapy with older therapy or inadequate support in the first attempt. Finally, after the implant there can remain a number of patients, perhaps as many as 25%, who are still not adequately treated and require attention and even inventive approaches of combined therapy to achieve therapeutic success not only for the sleep disordered breathing ^{15, 16}, but to address co-morbid sleep disorders (insomnia, poor sleep hygiene, REM behavior disorder, etc.) present after implantation.

HNS is a technology to stimulate a muscle known to decline in activation before an apnea ¹⁷. The nucleus of CNXII is in the brainstem, and is the motor nucleus for genioglossal coordination in not only breathing during sleep but in swallowing, talking, exercise, vomiting, hiccups, facial expressions, etc. This brainstem nucleus has efferent and afferent inputs to coordinate its actions^{18, 19}. Respiratory activation in the CNXII during sleep and wakefulness results from a coordinated network of neurons in the medulla, pons, and cortex. The nerve exits rather uniformly from the ventrolateral side of the medulla oblongata with motor and sensory roots, as well as contributing to the ansa cervicalis, and a discrete nerve bundle exits into the neck near the branching of the common carotid artery. Lateral to the hypoglossal muscle there is a division into the lateral and medial main branches ^{20, 21}. It is here that there is some phenotypic complexity, and outcome depends on the positioning for functional inclusion of protractors and exclusion of fibers that could retract the tongue mass ²². At the time of an electrode implant, recording electrodes are placed intraorally into the genioglossus and other muscles to monitor intraoperative stimulation, but the major outcome is observation of tongue movement. Therefore, normal functions of the genioglossus are important to assess in any patient being considered for HNS therapy.

The Inspire^® system management plan incorporates a procedure called drug induced sedation (or sleep) endoscopy (DISE). This procedure is not new being performed usually just before anatomic surgery, but it became used outside of the operating room for assessments of non-PAP alternatives and snoring ²³, and then for HNS ²⁴. In the development of the Inspire^® technology, it was the observation that the manner of closure of the velopharynx under moderate sedation had an impact on outcome. HNS treatment was successful in 81% of patients with an anterior-posterior pattern of velopharyngeal collapse on DISE, while treatment success was achieved in none of the 5 patients with complete concentric collapse ²⁵. This pattern of anterior-posterior collapse (like a garage door) being favorable, while a more concentric appearing collapse being less favorable for HNS has persisted ²⁶, and is a pattern also favorable for an oral appliance ²⁷. Higher BMI and higher AHI have been identified as parameters associated with a concentric collapse of the velum on DISE, but the correlation is modest at best ²⁸.

While patients undergoing DISE may have reductions in airway area at multiple regions under deep sedation, more often it is a collapse in the retropalatal greater than the hypopharyngeal region ²⁹. The pattern of anterior-posterior obstruction at the level of the velum cannot be predicted on the basis of other tests ³⁰. What determines this pattern of collapse and how it predicts to a significant degree therapeutic success is not known. One can imagine a number of intrinsic (airway mucosal folding, palatal orientation, tissue pressure, etc.) and extrinsic (airway wall fat, lung volume, etc.) factors.

A DISE carries additional risks and should not be performed in medically unstable patients. It is performed under moderate sedation, and there is a potential for oxygen desaturation or hypoventilation that may necessitate bag-mask ventilation or prolonged recovery from sedation, necessitating an extended post-procedure monitoring. On the other hand, the DISE procedure can be considered important in a CPAP intolerant patient as it can also be useful in identifying other anatomic problems like a lingual tonsil, prolapsed epiglottis or lack of evidence for success of an oral appliance. The risk benefit in this population for a DISE appears favorable.

Component Technology in the 2014 Approved FDA Device

HNS is approved for use in the United States as a FDA first-in-class therapy, available since 2014 as Upper Airway Stimulation from Inspire Medical Systems (Golden Valley, MN, USA). It is at the time of this reviews the only FDA-approved device. This implanted device works through placement of three stimulating electrodes in a cuff placed around the CNXII along its way to the tongue. The stimulation of this complex nerve activates extrinsic and intrinsic muscles of the tongue, but the intent is that either stabilization or forward movement keeps the tongue away from the back of the airway. Titration of the intensity (mAmp) is an empiric process, and an “advanced” setting can alter the anode and cathode configurations of the three cuff electrodes and the IPG. This is doen after titration when the initial electrode configuration fails. Nerve stimulation does not cause pain except if muscle contraction is intense, in contrast to stimulation of electrodes placed on or within the muscle which cause discomfort at the same time muscles are activated.

In the Inspire^® system the electrodes are activated by an implanted programmable generator (IPG). The IPG is programmed by an external tablet. A sensing lead for pressure changes within the chest informs the IPG when there might be a breath. This feature provides some degree of “feedback” to the IPG as to the phase of respiration (inspiration or expiration) and is used in the programing of the IPG to optimize the stimulation time across the timing of a breath, also called “duty cycle”. The system intended to stimulate upper airway opening at or near the point of a fall in intrathoracic pressure, i.e. the act of inspiration. Theoretically, one could save IPG power by synchronizing the pulse train with inspiration. All of these components are discussed in greater detail below.

The Inspire^® cuff electrode placed the hypoglossal nerve with the intent to activate the protrusor tongue muscles. There may occur other actions such as activation of intrinsic muscles changing the shape of the tongue, extrinsic pulling on the tongue, and a poorly understood forward movement of the anterior wall of the pharynx probably by action pulling the hyoid out by a vector of force on the hyoid apparatus ³¹. The surgical technique in general consists of an incision below the angle of the jaw in a natural crease and a direct approach to the hypoglossal nerve to achieve exposure in order to determine decisive placement of the cuff. ^{32, 33} The surgical training is to place a three-electrode cuff directly around the distal, medial branch, and tongue protrusion optimized intraoperatively for tongue protrusion and/or stabilization, as empirically determined during Phase II and Phase III FDA trials and in post-approval studies ^{15, 22, 33, 34}.

The Inspire^® IPG is inserted into a subcutaneous pocket ~4 cm below the clavicle, much like a cardiac pacemaker. The leads from the cuff electrode and the pressure sensor, respectively, are tunneled subcutaneously and then connected to the IPG. . The placement of the IPG for the HNS is usually within the soft tissues of the right upper chest; however, in the case of right-handed gun enthusiasts there are reports of left sided placement. Some are reluctant to place an IPG in a person who might anticipate blows to the chest as in fire rescue personnel or those in contact sports. There is a theoretical concern about HNS implants in those with cardiac or neural stimulation devices. A case report found a successful co-use of HNS with an implantable defibrillator ³⁵. However, post implant cardioversion is reported to disrupt functioning of the IPG. A retrospective case series concluded that there is a need to counsel for patients with HGNS undergoing external electrical cardioversion about the possibility of device damage, and either reprogramming or operative IPG replacement. Positioning the pad along an anteroposterior axis may help prevent such mishap. There is now a more general understanding of HNS in those who manage cardiac pacemakers and arrhythmia.

Another component in the Inspire^® system is a sensing lead placed thorugh a separate incision between the intercostal muscles in the fourth or fifth intercostal space ¹⁵. The pressure sensor lead is snapped in place into the IPG. The function of the sensor lead and the triggering of stimulation can be monitored wirelessly, and a time trace displayed on the programmer.

The Inspire^® “Advanced Settings” function permit the physician to change the anode and cathode configuration of the three electrodes and the IPG. The physician can also adjust to some degree the sensitivity and polarity of the pressure trigger. There is a patient-held device to turn it on or off, and within some pre-determined range the stimulus amplitude (strength) can be titrated by the patient at home. The patient remote also signals functions like “pause” or “length of “stimulation”, the later to turn off the device after a time (usually 8 hours) if the patient does not turn off the device at the end of sleep.

Clinical Data for the Inspire^® HNS device

The Stimulation Therapy for Apnea Reduction (STAR trial: ClinicalTrials.gov Identifier: NCT01161420) was the pivotal Phase III trial that led to FDA-approval of the Inspire^® device. Briefly, the most important features of this study are the inclusion and exclusion criteria, much of which was the outcome of the Phase II safety and efficacy study ²⁵. Hence, In the STAR trial exclusion criteria included body mass index (BMI) > 32, AHI <20 or >60, or central and/or mixed apnea index present in >20% of the AHI on polysomnogram (PSG); and as discussed above a pattern of complete concentric collapse at the level of the velopharynx observed with DISE.

The predetermined STAR endpoints were objective- AHI and the 4% oxygen-desaturation index (ODI)- and subjective- patient-based sleepiness and sleep related quality of life. At 12 months, 66% of participants were responders by AHI criteria, and 75% were responders by ODI criteria. As a quasi-control, at 12 months, 46 patients who had responded well were randomly assigned to either continue therapy or to a one-week cessation of stimulation. The latter resulted a change in AHI and symptoms towards pre-treatment levels ³⁶.

The 12-month FDA Phase III STAR trial was continued for 24-, 36-, 48- and 60-month outcomes ^36–39. At 5 years, Epworth Sleepiness Scale and quality of life was improved, with normalization of scores increasing from 33% to 78% and 15% to 67%, respectively. Objectively an AHI surgical response (AHI <20 events per hour and >50% reduction) occurred in three-quarters of the 71 subjects who consented for polysomnography at that time period. The responder rate was estimated at ~60–65% at 5 years, with all points at all follow-ups included; use was subjectively >80% of nights, in a group whose adherence to CPAP was 20% or less before implant. Serious device-related events all related to lead/device adjustments were reported in 6% of patients. Functional amplitude for stimulation were unchanged, as was the threshold for sensation. This supervised device trial found long-term benefit for individuals with moderate to severe OSA who have failed nasal continuous positive airway pressure ³⁹.

Post-Approval Studies.

The European Union approved the device in 2013, and the FDA in 2014. The FDA approval includes slightly modified criteria: BMI of 32 with a warning for those >32 to 35, an AHI >15 and <65, a predominance of obstructive apneas and hypopneas, and a predominant anterio-posterior pattern of collapse on a drug-induced endoscopy. At the present time there are at this time over 6000 implants performed worldwide.

The first reports outside of a clinical trial were from three German centers with training during the Phase III trial. In a prospective single-arm study, 6- and 12-month visits included Epworth Sleepiness Scale and home sleep testing as objective measures. In the 60 participants, the median AHI reduced from 28.6 to 9.5/hr from baseline to 12 months. Subjective outcomes improved significantly from baseline to 12 months. The average usage time was 39.1 +/− 14.9 hours per week based on recordings by the implanted device. One patient requested a removal of the device for cosmetic reasons, and this occurred without sequelae. This study was the first to utilize a follow-up plan using home sleep testing, and reported an independent cohort to indicate a safe and effective treatment option for patients with OSA in routine clinical practice ⁴⁰.

The FDA with the approval in April 2014 requested a follow-up registry from independent centers. There are now several interim reports which suggest that implants when criteria are generally met continue to show efficacy either equivalent or better to the STAR trial ⁴¹. Between October 2016 and January 2018, 508 participants were enrolled from 14 centers. Median AHI was reduced from 34 to 7 events/hr; and median ESS reduced from 12 to 7 from baseline to final visit at 12-month post-implant. For each 1-year increase in age, there was a 4% increase in odds of treatment success. For each 1-unit increase in body mass index (BMI), there was 9% reduced odds of success. Age persisted in a multivariate model as a significant predictor of treatment success, and age was directly assessed in another analytic approach ⁴². The more subjective and objective use, the better the patient-centered outcome ⁴³. A recent report on 1000 patients that the therapy effect is durable and adherence is high.

There is only one study of potential effects of HNS on cardiovascular risk. Blood pressure was examined in a retrospective study in regard to the consequences of therapy ⁴⁴. Mixed-effect models were used to compare outcomes at 2 to 6 months in 201 patients in each arm after propensity matching. Results were adjusted for therapy adherence. PAP showed greater improvement in blood pressure, but HNS was associated with greater improvement in sleepiness symptoms. Results need to be confirmed in studies of better experimental designs.

Other HNS Devices in Trials.

Currently the most experience is with an FDA approaved HNS device marketed by by Inspire Medical Systems (Golden Valley, MN, USA). The 12-month FDA Phase III Stimulation Therapy for Apnea Reduction (the STAR trial) was continued for 24-, 36-, 48- and 60-month outcomes ^36–39. Since that trial Inspire Medical Systems has replaced the first with a second generation IPG that has advanced features for programming and for monitoring of patient use with a display more like that of PAP adherence. This device is compatible with MRI imaging of the brain and is being assessed for safety in MRI imaging of other body areas. The patient remote is now in its second generation with improved design, and a capacity to follow therapy use, timing, and remote reporting of this data. It components are described above.

Currently there are three other devices, which reported clinical trials at one level or another. None have been compared to each other and none have long-term safety and efficacy reports. Direct comparison of the stimulation paradigms has not been done. Almost at the same time as the Inspire^® device, (Apnex Medical, St Paul, MN, USA) began a sequence of clinical studies towards a goal of FDA approval. The technology was based on HNS delivered to a cuff placed on the main trunk of CNXII, more proximal to that described for Inspire^®, and had an IPG neurostimulator and two respiratory sensing leads (impedance technology) used to synchronize stimulation to inspiration. Selection was based on patient-derived information and the polysomnogram with predominantly obstructive hypopneas rather than apneas, and a DISE examination was not part of the inclusion profile. The stimulation profiles for the cuff electrodes are not detailed and IPG programming is for pulse width, frequency, current amplitude. Imaging studies suggested that the effect was to increase the oropharyngeal and retropalatal dimensions. This device looked promising in Phase II safety and efficacy trials ⁴⁵. There were patients who did extremely well and the mean fall in AHI in 31 moderate to severe patients was 45%. However, the FDA pivotal Phase III trial (ClinicalTrials.gov Identifier: NCT0144660) was terminated early by the company given a likelihood that efficacy outcomes might not be met. No comparisons are available to other therapy or technology.

The aura6000 by LivaNova (formerly ImThera, San Diego CA) is currently in the midst of a Phase III clinical trial (THN3: ClinicalTrials.gov Identifier: NCT02263859). This device places a 6-electrode cuff on the trunk of CN XII ^{46, 47}. This does not have a synchronizing trigger but rather the device cycles stimulation across the different electrodes continuously in order to activate muscles of the tongue to open the upper airway during sleep. A DISE is not required for eligibility. The device is programmed through a physician’s computer. The reported Phase II trial found a reduction in AHI in AHI of 53%, selection based solely on patient information and the polysomnogram ⁴⁸. A case series report suggested that turning off the device did not rapidly result in a return to baseline AHI levels, implying a training effect or improvements in upper airway function when obstructions in sleep are improved ⁴⁹. This result has not been replicated, and was not obvious in the one week withdrawal study of the Inspire^® device³⁶. Whether this is a unique feature to this device is not known.

The Nyxoah SAT system (Belgium) in clinical trials deploys bilateral implantation of very small electrodes at the insertion of the CN XII into the base of the tongue, and is externally charged and controlled by a disposable patch, worn on the patient’s chin. It is approved for use in Europe. There are reports to suggest safety and efficacy ⁵⁰. A critical FDA Phase II-III efficacy trial (ClinicalTrials.gov Identifier: NCT02312479) was terminated in April 2016, but is reported to restart.

A comparison of the general characteristics for the four devices is provided in Table 1. For each device there is an external method for programming the IPG settings for stimulus strength or intensity (mAmp), stimulus pulse frequency and duration, duration of the pulse train, and, in those two with closed-loop sensing from a respiratory signal, a triggering of the pulse train, intended to synchronize with inspiration.

Table 1.

Technology in Nerve Stimulators available in the literature

Device	CN XII Placement	Power Source	Feedback	Approval Status 2019
Inspire	medial branch one side	IPG	Pleural Pressure	CE* and FDA
Apnex	Medial branch, one side	IPG	Impedance	CE but not FDA, Withdrawn from ClincialTrials.gov
Aura6000 (Imthera)	Main Trunk, one side	IPG	None	CE but no FDA
Nyxoah	Distal at the branches that enter to the muscle, bilaterally	External submental device wirelessly powering the stimulator	None	CE but not FDA, Withdrawn from ClincialTrials.gov

^*European approval which permits the marketing of the device

There are two meta-analyses of all clinical data from the available HNS studies from the four devices investigating objective and subjective outcomes, and side effects ^{51, 52}. How independent they are is not known as each report examined data from 16 studies and 381 patients, and the methodology was common one- a comprehensive literature search of PubMed and Scopus and examination of papers meeting criteria (objective and subjective outcomes and adverse events) by two independent reviewers. In this review the mean AHI was reduced by 21/hr (95%CI, 16.9–25.3), mean ODI was reduced by 15/hr (95%CI, 12.7–17.4), mean ESS was reduced by 5 (95%CI, 4.2–5.8), mean FOSQ improved by 3 (95%CI, 2.6–3.4).

Considerations of Cost is only available for the Inspire^® device. In one report, the estimated lifetime incremental cost effectiveness ratio (ICER) of $39,471 per quality-adjusted life year (QALY) for patients meeting the STAR inclusion criteria ⁵³. This cost is less than the currently accepted cost-effectiveness threshold in the United States of $40–50K/QALY, but more than CPAP, which has an ICER of $15,915/QALY. However, for the US patient there may occur out-of-pocket costs for deductibles and co-pays for assessments prior to implantation. In particular, the DISE procedure may not result in the identification of the patient as an ideal candidate. Relative to other implants Nyxoah has an external power source, and the argument is that over an expected device lifetime, cost might be reduced by 33%.

Experiences with Inspire^® in Selected Clinical Populations

One of the first reports of a commercial implant involved a case of a patient with persistent symptoms and findings of OSA, including an AHI >30/hr, who responded to HNS to an AHI of <10 despite a history of multiple multilevel procedures, including an uvulopalatopharyngoplasty (UPPP) with revision, a genioglossus advancement, and a maxillomandibular advancement ¹⁴. The post-award registry (ADHERE) was queried as to whether previous palate or hypopharyngeal surgery was associated with efficacy of treatment of obstructive sleep apnea ¹⁶. For this analysis, outcomes were defined by the apnea-hypopnea index (AHI), in 3 ways: change in the AHI and 2 definitions of therapy response requiring >/=50% reduction in the AHI to a level <20 events/h (Response20) or 15 events/h (Response15). Previous palate and hypopharyngeal (tongue, epiglottis, or maxillofacial) procedures were documented. Any previous surgery, previous palate surgery, and previous hypopharyngeal surgery were not clearly associated with a better treatment response; (0.69– 95% CI: 0.37, 1.27) odds of response (Response20 measure) at therapy titration and a 0.55 (95% CI: 0.22, 1.34) odds of response (Response20 measure) at final follow-up. A case series from one German center confirmed this lack of effect of prior surgery and post-implant efficacy of surgery in non-responders after HNS implant. The implications are that upper airway surgery should be considered in patients with persistent OSA after UAS implantation if the obstruction is identified at the level of velum and oropharynx. However, upper airway surgery during an assessment for implantation may not improve HNS outcomes ⁵⁴.

Inspire^® has a research exception approval for a clinical trial in those with Downs Syndrome (DS). Obstructive sleep apnea (OSA) affects up to 60% of those with DS and will persist in 50% after adenotonsillectomy. This group of patients often do not accept positive pressure airway support devices or tracheotomy for their residual moderate to severe OSA. In the initial pilot study of 6 adolescents, HNS placement reduced AHI below 2 in 2 patients and >56% in the others, accompanied by improvements in the quality of life of the child and the parent ⁵⁵. A report of 20 patients was recently reported similar results as well as documented ~9.2 hours of nightly use ⁵⁶. This has potential for being a therapeutic option. There are no reports of HNS in OSA pediatric patients without development challenges or with residual AHI after adenotonsillectomy.

There are no prospective analyses to compare this technology to established therapy or to another therapy. This will be difficult to do from an industry perspective and has some intrinsic problems. The population for HNS is very selective, so that matching on patient characteristics based on HNS criteria can be problematic. One cannot select as a control those that refuse therapy as creates a potential for a “hidden bias” of patient motivation and physician management. Nevertheless, there are reports of such attempts.

One is a comparison of UPPP vs. Implant with AHI as the outcome. In one ⁵⁷, AHI outcomes were compared between implant patients with moderate to severe OSA who underwent HNS surgery (Inspire Medical Systems) and an historical cohort those who had underwent traditional airway reconstructive surgery, specifically uvulopalatopharyngoplasty (UPPP). Both traditional surgery and HNS were effective in patients with moderate to severe OSA with CPAP intolerance, but HNS to an AHI of <5 occurred more often in HNS.

Another is a comparison of transoral robotic surgery vs. HNS. One retrospective chart review identified and compared patients with BMI and AHI criteria for HNS who either had HNS or anatomic surgery. Defined as AHI < 5, the outcomes with HNS was ~70% and with robotic surgery ~10%. Studies like this are need to develop and evaluate treatment algorithms such as a staged approach to CPAP-intolerant patients seeking surgical management of OSA ⁵⁸.

Risks and Adverse Events in this Therapeutic Class

In all the reports of all devices, the most common risks are those associated with the implantation ^{51, 52}. If underlying health and medical conditions exist, such as those which put one at higher risk for any surgery, then this technology might not be a good option. As with any surgery, there is a short-term risk. Patients with chronic conditions like platelet disorders or immunodeficiency should be considered ineligible or proceed carefully in a case-by-case basis.

Up to this time, there have been no deaths at implant, which is attributed to the selection of medically stable patients who have not had serious illness or hospitalization for at least 6 months, and to physician training, preparation, and post-operative team management. Procedures in the United States are same-day procedures, unless there occur surgical complications. There are a handful of patients who might require overnight monitoring, for instance to observe after evacuation of a post-operative hematoma or a slow recovery from general anesthesia. Pain at the incision site is mild to moderate, mitigate in days, and when compared to UPPP is minor in nature ⁵⁷.

Reported adverse events are minimal and not life threatening. The side effects are mainly in the outpatient post-operative period. The only complication specific to the mechanism of the device is a post-operative, temporary tongue weakness reported in ~20%, and most resolved spontaneously within a week, the longest being 1 year. Bleeding and infection in the post-operative period can be managed by those with experience with implanted devices in general. Three Inspire^® HNS devices were explanted-two due to discomfort, and one due to septic arthritis. The abstract presentations on the Apnex Medical device reported that devices were explanted without problems after the failed Phase III trial. Between 12 and 48 months two Inspire^® patients required procedures to address sensing lead displacement. Longer-term risks in ADHERE were repetitive tongue stimulation include soft tissue abrasions, discomfort with electrical stimulation, and dry mouth ^{39, 59}. Pain (6.2%:0.7–16.6), tongue abrasion (11.0%:1.2–28.7), and internal (3.0%:0.3–8.4)/external device (5.8%:0.3–17.4) malfunction were adverse events reported across all studies ^{51, 52}.

The stimulator could potentially dysfunction. The handheld patient controller battery depletes, and can deplete quickly especially if it is carried about during the day as it is movement activated. This problem is common and a workaround is to remove the AAA battery when travelling. In <1% of implants there is a problem with a lead. The nerve electrode would dislodge from the IPG 12- to 18-months after implant in first generation models; however, the current device has an improved connector required close attention to tightly sit in the IPG. There can be a dislodgement of the sensing lead from the extrapleural space. This may occur with trauma to the chest. The pacer may also fire or activate inappropriately, leading to discomfort during wakefulness, but this is usually because the device is left on or is activated by the remote as it is carried in a pocket or moved about the house. The functions of an activation delay upon starting and the “Pause” function make it appear that the activation is spontaneous when it is not. The IPG battery will eventually fail, requiring another surgery to replace the unit. This has been done in several who were in Phase II or II trials of Inspire^®. Table 2 is a checklist for the physician in the event the devise stops working entirely.

Table 2.

Examples of Troubleshooting of the Inspire Medical Systems Device

Problem	Actions
Remote does not turn on the device.	Check Battery level and Patient comprehension of “Delay” and Pause” functions…..if OK, proceed to check the IPG
Failure to activate	Check with IPG programmer for stimulus settings and test thresholds
No capture with maximal pulse level	Check sequence of sensing and pulse generation (Inspire® system) and if the IPG senses and creates a stimulus the problem is in the lead
Stimulation “too much” for patient	Within 8–10 weeks of implant, there is resolution of swelling around the electrode and thresholds will have dropped. Adjust thresholds
Stimulation “too much” for patient	Titrate thresholds and try to recreate the sensation. If present, can adjust with “Advanced Settings” the electrode configurations
Works fine until morning when snoring reoccurs	May result from muscle fatigue, adjust stimulus intensity or change electrode setting to get the same tongue movement with less intensity

State of HNS outside of Europe and the United States

In June 2018, one the Inspire Medical Systems device was been approved by Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. PMDA is like FDA in the US and is working together with Ministry of Health, Labour and Welfare. After this approval, guideline committee members selected from 4 major societies, The Japanese Respiratory Society, The Japanese Circulation Society, The Oto-Rhino-Laryngological Society of Japan, and The Japanese Society of Sleep Research, discussed about eligibility criteria for this new therapy in Japan and already submitted it to the Ministry of Health, Labour and Welfare. At this point, Ministry of Health, Labour and Welfare is working on insurance reinvestment issues according to the submitted guideline. In the quite near future, HNS will be available in Japan, the first country in Asia. Japanese otolaryngologists are preparing to deploy a HNS device at training sessions with experienced otolaryngologists from the USA and Europe.

Interest is there is other countries but at present there are no referral centers outside of Europe and the United States that have committed to the training and the coordination of care required to be successful with this therapy.

Conclusions

In general, the Inspire^® HNS can significantly reduce AHI in moderate-to-severe OSA patients, and produce symptom relief, given certain inclusion and exclusion criteria. As yet is only device which has extensive publications and approval in both the US and Europe. However, the reports from Phase II trials of three other devices appear to provide support that this line of therapy works in selected patients. In the large Inspire^® cohorts, CPAP-non responders with a lower BMI (~32 or less), an AHI <65, and a favorable anterior-posterior pattern of velopharyngeal collapse on DISE do better. Despite strict inclusion criteria, up to one-third of CPAP-intolerant patients may not fully respond to Inspire^® HNS therapy by Sher AHI criteria. Adverse events are not serious and post-implant use profiles are ~80% suggesting a reasonable risk-benefit for patients in whom CPAP therapy is not used.

Limitations to widespread adoption of Inspire^® HNS therapy include the relative invasiveness of a new procedure, the cost of the device, and the requirement for preimplantation DISE. In comparison, CPAP and oral appliances when used are relatively cost-effective and non-invasive when successful. For these reasons, HNS is not currently considered a first-line treatment option. HNS therapy, however, should be considered as one alternative therapeutic option for patients meeting the inclusion criteria when more traditional therapeutic options have been considered.

Figure 1.

Shown is an illustration of the anatomic site of collapse (left) and a recording of an obstructive apnea (right). A full or partial collapse occurs most commonly along the airway form the nasopharynx to the epiglottis) resulting in apnea or hypopnea, respectively. The mechanism initiating this physiology is a reduction in neuromuscular drive (red arrows). There is a fall in genioglossus EMG activity (large red Arrow) occurring as flow reduces and then ceases despite efforts as indicated by the negative swings in esophageal pressure. The pressure swing are reduced at the beginning of the apnea but then start to increase as efforts persist until there is a large activation in EMG activity with arousal and opening of the airway as evidenced by resumption of flow.

Figure 2.

Shown are the components of the Inspire Medical System HNS device. There is the stimulation lead placed on the medial branch of the hypoglossal nerve, the pulse generator (IPG) placed ~4 cm below the clavicle, and the breathing sensor place din an intercostal space next to the pleura. The patient remote is shown outlined in red. Not shown is the physician table for programming the IPG. Illustration and inserts are courtesy of Inspire Medical Systems.

Figure 3.

Shown is the physiologic response when the stimulator is OFF vs ON. There are 3 obstructive hypopneas with subsequent falls in oxygen saturation before the device is turned ON and more regular breathing is restored. EOG: electrooculogram, EMG= submental electromyogram, EEG: electroencephalography, SaO2= oxygen saturation.

Figure 4.

These are CT scans of the airway at midline at Baseline (left) and with stimulation (right). The red arrows point to the regions of the nasopharynx and oropharynx, respectively. There are notable increases in the A-P airway in both regions. Images are courtesy of Dr. Jan DeBacker.

Figure 5.

Shown is a panel showing a cross-sectional map of the areas behind the Palate and at the tongue base and the 4 panels representing pairs of Palate and pairs of tongue base images with therapy OFF or ON. Labels orient the pictures to the anatomy. HNS activation increases the cross sectional area both behind the palate and behind the tongue. Source: Inspire Systems Training materials, by permission.