DRAFT JCSM Special Edition ARedits updated PDF

Table of Contents FOREWORD .............................................................................................................................................................................. 2 POPULATION HEALTH: SLEEP APNEA.....................................................................

Table of Contents FOREWORD .............................................................................................................................................................................. 2 POPULATION HEALTH: SLEEP APNEA....................................................................................................................................... 2 CARDIOVASCULAR DISEASE & SLEEP APNEA ........................................................................................................................... 3 UPPER AIRWAY STIMULATION: HISTORY AND CURRENT STATE ............................................................................................. 4 CLINICAL OVERVIEW ................................................................................................................................................................ 4 STIMULATION THERAPY FOR APNEA REDUCTION (STAR) CLINICAL TRIAL.......................................................................... 4 ADHERE (Adherence and Outcome of Upper Airway Stimulation (UAS) for OSA International Registry ........................... 5 CLINICAL TRIALS IN PROGRESS ............................................................................................................................................ 6 Utilization of Home Monitoring during therapy optimization in patients with an Inspire UAS...................................... 6 Effects of Hypoglossal Nerve Stimulation on Cognition and Language in Down Syndrome and OSA ............................ 6 PATIENT SELECTION & EVALUATION ....................................................................................................................................... 7 HYPOGLOSSAL NERVE IMPLANT CARE PATHWAY ............................................................................................................... 7 INDICATIONS ........................................................................................................................................................................ 7 DIAGNOSTIC TESTING .......................................................................................................................................................... 8 WEIGHT MANAGEMENT & BMI ........................................................................................................................................... 8 SLEEP CO-MORBID CONDITIONS ......................................................................................................................................... 9 PATIENT SELECTION AND RISK STRATIFICATION ............................................................................................................... 10 PATIENT EDUCATION & EXPECTATION MANAGEMENT .................................................................................................... 10 ENT EVALUATION ........................................................................................................................................................... 10 ENT CONSULTATION .......................................................................................................................................................... 10 DRUG-INDUCED SLEEP ENDOSCOPY: DISE......................................................................................................................... 11 PRE-SURGICAL PLANNING.................................................................................................................................................. 12 HYPOGLOSSAL NERVE PROCEDURE ....................................................................................................................................... 12 SURGICAL IMPLANT ........................................................................................................................................................... 13 ADVERSE EVENTS AND COMPLICATION MANAGEMENT .................................................................................................. 13 THERAPY OPTIMIZATION ....................................................................................................................................................... 15 ACTIVATION AND ACCLIMATION ....................................................................................................................................... 15 ADVANCED MANAGEMENT ................................................................................................................................................... 17 Awake Endoscopy with Advanced Titration to Optimize Upper Airway Stimulation ....................................................... 17 INSOMNIA POST-IMPLANTATION ...................................................................................................................................... 16 LONG TERM MANAGEMENT .................................................................................................................................................. 18 COLLABORATIVE CARE TEAM APPROACH AND SHARED DECISION MAKING WITH THE PATIENT.................................. 20 ROLE OF DENTAL SLEEP MEDICINE IN THE 21ST CENTURY..................................................................................................... 21 FUTURE DIRECTION................................................................................................................................................................22 PROGRAM PROFILE: CARE COORDINATION ......................................................................................................................... 22 Relevant HNS Publications ..................................................................................................................................................... 23 BIBLIOGRAPHY ....................................................................................................................................................................... 24 AUTHORSHIP EDITOR-IN-CHIEF Asim Roy, MD REVIEWING AUTHORS MAURITS S. BOON, MD SHALINI MANCHANDA, MD Vice Chair of Education | Associate Professor Otolaryngology | Sleep THOMAS JEFFERSON UNIVERSITY Medical Director | Professor Sleep | Pulmonary | Critical Care INDIANA UNIVERSITY AMIT PATEL, MD FCCP, ABIM Medical Director Sleep | Pulmonary | Critical Care VIRGINIA HEART SLEEP CENTER CONTRIBUTING AUTHORS (in order of sections) ASIM ROY, MD KEVIN FABER, MD AMIT PATEL, MD Medical Director Sleep | Neurology OHIO SLEEP MEDICINE INSITITUTE Chief Medical Officer Sleep | Neurology SANFORD HEALTH Medical Director Sleep | Pulmonary | Critical Care VIRGINIA HEART SHALINI MANCHANDA, MD RAMI KHAYAT, MD RADHIKA BREADEN, MD Medical Director Sleep | Pulmonary | Critical Care INDIANA UNIVERSITY Medical Director Sleep | Pulmonary | Critical Care UCI HEALTH Medical Director Sleep | Internal Medicine | Obesity PACIFIC SLEEP PROGRAM MICHELLE DRERUP, PSYD KIRK WITHROW, MD EUGENE CHIO, MD Director of Behavioral Sleep Medicine Sleep Psychiatry CLEVELAND CLINIC Medical Director Otolaryngology UAB MEDICINE Medical Director Otolaryngology THE OHIO STATE UNIVERSITY CHRIS LARSEN, MD NOAH PARKER, MD MOHAMED SALTAGI, MD Medical Director Otolaryngology KU MEDICAL CENTER Medical Director Otolaryngology INDIANA UNIVERSITY Otolaryngology Resident INDIANA UNIVERSITY YELENA CHERNYAK, PhD VIKAS JAIN, MD Medical Director Sleep | Family Medicine HARMEET CHIANG, DDS Director of Behavioral Sleep Medicine Sleep Psychiatry INDIANA UNIVERSITY DREAM SLEEP MEDICINE DAVID MOORE, RPSGT, CCSH Clinical Director University Sleep Disorders Center UAB MEDICINE 1 Assistant Professor Sleep Dentistry VCU HEALTH FOREWORD Editor in Chief: ASIM ROY, MD “Imagination is more important than knowledge. For knowledge is limited, whereas imagination embraces the entire world, stimulating progress, giving birth to evolution.” -Albert Einstein I have been practicing sleep medicine for over 15 years and entered the field by chance. Restorative sleep has become my passion and has been inspired by some of the pioneers in our field. I could not see myself doing anything else. The impact of sleep on the multitude of other diseases and organs is astonishing. We have a global epidemic on our hands with obstructive sleep apnea (OSA) and need a variety of tools to treat this complex disease. This publication aims to provide additional information and shed light on how hypoglossal nerve stimulation is not only a second-line treatment option, but also a very effective option. While co-morbid diseases can impact outcomes with all OSA treatments, patient selection for Upper Airway Stimulation (UAS) also known as Hypoglossal Nerve Stimulation (HNS) therapy is critical to manage these complex patients. I was honored to be asked to be the editor of this article and want to thank all the authors involved with their dedication to advancing our field. POPULATION HEALTH: SLEEP APNEA The precise definition of the term population health is not yet fully agreed upon, though the proposed definition by Kindig and Stoddart [1] includes the health outcomes of a group of people, including the distribution of those outcomes within the overall group. It refers to a systematic approach to health and wellness that seeks to efficiently improve the health of a population. Knowing who is potentially unhealthy and requires evaluation and efficiently delivering necessary testing and treatment of those individuals can lead to improvement in overall health outcomes of the population (Figure 1). Simply stated, the goal of population health initiatives is to use the right form of care, in the right person, at the right time. Applied to the diagnosis of sleep apnea, the goal is to evaluate and treat the highest risk people as efficiently as possible to improve overall health for the targeted group. The Institute for Healthcare Improvement proposed the Triple Aim that centered around three overarching goals [2]: • • • Improving the patient experience of care that includes quality and satisfaction Improving the health of populations Reducing the per capita cost of healthcare Since the initial framework, a fourth goal has been integrated within some frameworks that includes creating an environment that improves healthcare workforce satisfaction to address provider burden and burnout [3] 2 Given the prevalence of sleep apnea, which ranges from 15-30% in men and 10-15% in women [4, 5], its greater prevalence in African Americans versus Caucasians at the same age and body mass index [6, 7], and its increasing incidence within the population over time [8], coupled with the generally accepted higher risk of various metabolic, cardiovascular, cerebrovascular, neurocognitive, and psychiatric conditions with untreated sleep apnea, it is becoming progressively more important to identify those at risk to evaluate and provide a treatment plan. In 2016, AASM commissioned a report for the United States (U.S.) that estimated prevalence of OSA [Apnea Hypopnea Index (AHI) >5] as approximately 29.4m lives with only 5.9m (20%) of patients formally diagnosed, leaving approximately 23.5m patients undiagnosed. These patients are at risk of developing ongoing chronic conditions that may ultimately impact quality of life, increase cost burden to the health system, and decrease societal contribution of these individuals [9] . The impact of untreated sleep disordered breathing to the health system is estimated to be ‘approximately 8 additional office visits, 18 additional prescriptions, and an incremental increase in healthcare expenditures of almost $7000 per individual per year,’ with the overall direct health care cost estimated to be $94.9 billion [10] The use of artificial (augmented) intelligence algorithms to assist, but not replace, the scoring of sleep studies shows promise to improve efficiency and accuracy [8], as does its emerging use as a predictive analytics as a population health screening tool embedded within electronic medical record systems [11, 12]. The use of such tools has the potential to dramatically impact population health by rapidly screening more people and identifying those at highest risk and greatest need for diagnostic testing, though ethical, legal, and logistical dilemmas still exist. CARDIOVASCULAR DISEASE & SLEEP APNEA Cardiovascular disease (CVD) is a leading cause of both morbidity and mortality around the world and continues to increase over time [13], with OSA widely prevalent within this population [14]. Patients with drug resistant hypertension, atrial fibrillation, congestive heart failure and coronary artery disease have particularly high comorbid OSA with rates of 83%, 49%, 36% and 30%, respectively [15-18]. Treatment of sleep apnea has been noted to abate negative cardiovascular outcomes in certain disease states, and research is ongoing in this arena. The effect of OSA on cardiovascular disease is multifactorial, including key factors such as intermittent hypoxemia, autonomic fluctuation, and intrathoracic pressure swings. The combination of these factors can create both acute and chronic sequelae on the cardiovascular system. Intermittent nocturnal hypoxemia has been linked to elevated blood pressure levels, systemic inflammation, vascular endothelial dysfunction, and adrenergic stimulation[19-22]. Mann et al demonstrated the cardiotoxic effects of adrenergic stimulation [23]. During sleep apnea events, inspiration against a closed upper airway creates negative intrathoracic pressure, subsequently affecting blood volume distribution and causing physiologic stretching of the myocardium. The latter effect can compromise cardiac function and electrical rhythm[24-27]. For example, in patients who underwent elective catheter ablation for symptomatic atrial fibrillation, CPAP therapy for OSA resulted in a greater than two-fold improvement in atrial fibrillation-free survival post-procedure when compared to patients with untreated OSA, and atrial fibrillation-free survival rates similar to patients without underlying OSA [28]. In another study, withdrawal of CPAP therapy for OSA led to an increase in morning blood pressure and urinary catecholamines [29]. Given the strong correlation between sleep apnea and CVD, more robust screening and treatment of modifiable factors is imperative. Identification and treatment of comorbid OSA appears to be helpful in the reduction of morbidity and mortality for certain cardiovascular conditions. The America Heart Association recently updated recommendations for general screening of OSA for patients with certain cardiovascular conditions such as poorly controlled hypertension, recurrent atrial fibrillation and pulmonary hypertension [21]. 3 In addition, the Heart Rhythm Society highlighted the need for collaboration between cardiovascular and sleep medicine teams, suggesting that such interdisciplinary relationships may play a key role in the development centers of excellence for atrial fibrillation[30]. The link between OSA and CVD continues to support the notion that treatment of sleep disordered breathing is essential to cardiovascular and population health management. UPPER AIRWAY STIMULATION: HISTORY AND CURRENT STATE Early studies from the 1990’s demonstrated that hypoglossal nerve stimulation (HNS) was capable of keeping the airway open during sleep in OSA patients. [31] Inspire Medical Systems (Golden Valley, MN) was the first company to complete pivotal trials by late 2013. In the U.S., FDA approval was received in 2014, and indicated as a second line treatment option for patients who failed or struggled with CPAP. The Inspire therapy system comprises of 5 components (Figure 2): • • • • • Stimulation Lead Implantable Pulse Generator Respiratory Sensing Lead Sleep Remote Inspire Programmer & Cloud Since that time, several aspects of the therapy have evolved including: • • • Figure 2. Inspire Therapy System Surgical Technique Evolution from 3-incision to 2-incision [32] Procedural Location Transition for less complex patients from a hospital operating room (OR) setting to an ambulatory surgical center (ASC) setting when available [33] Insurance Coverage As a second line treatment option, insurance approval has expanded to cover 260 million lives and includes most major commercial insurance and Medicare [34]. CLINICAL OVERVIEW Since the 2014 FDA approval of the Upper Airway Stimulation (UAS) device in the U.S for the treatment of obstructive sleep apnea, there have been over 20,000 Inspire UAS implants worldwide [35]. Studies are underway to continually gather data on the effectiveness of treatment in real-world settings, as well as to streamline patient care. STIMULATION THERAPY FOR APNEA REDUCTION (STAR) CLINICAL TRIAL The STAR pivotal trial was a multi-center, prospective trial with a 12-month single arm study and a randomized controlled therapy withdrawal study at 13 months [36]. The study enrolled 929 OSA patients. These patients were evaluated against patient selection criteria that included moderate to severe OSA, a BMI (body mass index) less than or equal to 32, and the absence of a complete concentric collapse at the level of the soft palate. Following the evaluation period, 126 patients met all selection criteria and proceeded to implant. All 126 implant procedures were successful, and 124 of the 126 implanted patients provided evaluable data through at least 12 months. The STAR trial was an intent-to-treat study. Therefore, the 2 patients who 4 did not provide evaluable data through 12- and 18-months post-implant are assumed to be non-responders and were included in the evaluation as such. The patients' baseline AHI showed a mean of 32.0 and a median of 29.3, and the baseline ODI showed a mean of 28.9 and a median of 25.4. The primary outcome was the change in the severity of OSA as assessed by AHI and Oxygen Desaturation Index (ODI) at 12 months, post-implant. The co-primary outcome was the proportion of responders, defined as an AHI reduction of at least 50% from baseline and less than 20 events per hour, and an ODI reduction of at least 25% on the 12-month polysomnography (PSG). Secondary outcome measures included self-reported sleepiness and disease-specific quality of life as assessed by the Epworth Sleepiness Scale (ESS) and the Functional Outcomes of Sleep Questionnaire (FOSQ), and the percentage of sleep time with oxygen saturation ≤90%. The STAR study met all primary endpoints, demonstrating significantly reduced AHI to mild levels (29.3 events/hour at baseline to 9.0 events/hour at 12-months, p < 0.001), and a similar reduction in ODI (25.4 events/hour at baseline to 7.4 events at 12-months, p<0.001). At the 12-month visit, the first 46 consecutive responders were randomized (1:1 ratio) to a therapy maintenance group or a 7-day therapy withdrawal group. Polysomnography was performed to measure the effects of therapy withdrawal as compared with therapy maintenance. Patient symptoms measured by the ESS and FOSQ also showed significant improvements, with FOSQ change of 2.9, exceeding the 2.0 point clinically meaningful improvement, and reduction of ESS from 12 to 7 (p < 0.001). Longer follow-up of this same cohort demonstrated the reduction of AHI was stable and durable through 5-years, with AHI remaining at 6.2 events/hour and patient-reported outcomes FOSQ and ESS remained similar to the 12-month outcome [37]. Subjects were then followed annually through five years post-implant, representing one of the longest follow-up periods of a surgical sleep apnea therapy. ADHERE (Adherence and Outcome of Upper Airway Stimulation (UAS) for OSA International Registry ADHERE is an ongoing international, multi-center, prospective, observational registry designed to collect clinical evidence, effectiveness, use and safety in a group of properly trained programs in a real-world setting. Data is collected retrospectively and prospectively for the registry. The registry started in October 2016 with the expected completion date of September 2025. The primary outcome measures are changes to AHI and ESS from baseline to 12 months. The secondary outcome measures are patient experience with therapy, therapy adherence (hours of use per week), advanced or additional titrations (in-office or sleep laboratory device titrations), and physical assessment [blood pressure and body mass index (BMI)], Clinical Global Impression – Improvement scale (CGI-I), device data collection and change in the insomnia severity index (ISI). As of January 2022, over 3,700 patients have been enrolled in the registry across 60 centers in the U.S. and Europe. There have been multiple publications from the ADHERE registry, which has informed many aspects of therapy outcome in a real-world setting with larger sample sizes than the original STAR trial. The first set of publications (1-2) demonstrated that the real-world results post-approval are similar to the pivotal study, with additional data showing at least 90% patient-satisfaction rates compared to previous CPAP experience, and physician-reported outcomes using the CGI-I reporting over 90% clinical improvement as compared to baseline. Other key learnings have demonstrated that female gender and lower BMI are predictive of higher-than-average therapy response, highlighting potential anatomical or physiological mechanisms of UAS OSA treatment beyond opening the airway. The ADHERE registry has demonstrated therapy efficacy in populations beyond those treated in the original trial. For example, a sub-analysis was used to demonstrate therapy efficacy in an older population aged 65 [38] and showed that 5 older patients had improved AHI reduction and higher usage than a younger population. Furthermore, surgical adverse events were 1%, maintaining procedural safety despite advanced age. These data were used to support national Medicare reimbursement for UAS, which was granted in 2020. Most recently, the registry was utilized to report outcomes in patients with higher BMIs than those included in the STAR Trial (BMI 32-35 versus <32) [39]. This analysis demonstrated that both groups had significant reductions in their AHI and ESS. Patients with BMI <32 had a higher Sher responder rate than those with BMI 32-35 (72 vs 60, p =0.02), and higher therapy usage (5.8 ± 2.0 hours/night vs 5.2 ± 2.2, p = 0.028)[40] . Lastly, the registry was utilized to compare outcomes after improvements in implantation technique. The original implantation method required three incisions (sensor, generator, and stimulation lead), which was further improved to reduce to two incisions and leveraging the generator pocket as the location for placing the sensing lead to the second intercostal space. This sub-analysis compared propensity-score matched 3-incision cohort (n=404) versus the 2-incision cohort (n=223) and demonstrated that the 2-incision technique reduced operative time by 33% (129 to 87 min, p < 0.001), with comparable low adverse event rates. Patient outcomes including post-operative AHI and ESS were similar across both surgical approaches. In 2021, these results led to FDA approval of the 2-incision technique. CLINICAL TRIALS IN PROGRESS Utilization of Home Monitoring during therapy optimization in patients with an Inspire UAS The current recommended protocol for patients after UAS therapy activation is an in-laboratory titration PSG. As some patients arrive at the PSG at therapeutic amplitudes, it is hypothesized that HSAT could be a non-inferior alternative, and reserve PSG for patients who may have mixed results from HSAT. Also known as the HOME study, the goal is to compare the outcomes of two post-implant care algorithms to determine HSAT may be used in place of in-laboratory PSG titration in patients. Subjects (maximum, n=100) will be randomized (1:1) to undergo either HSAT or in-laboratory PSG. The control arm will undergo an in-laboratory titration PSG three months post activation, followed by a two-night HST six months post-activation. The active study arm patients will undergo a two-night HST three months post-activation, followed by an in-laboratory titration study if any interventions are required to optimize therapy. Similar to the control arm, the active study arm patients will have a two-night HST six months post-activation. As of January 2022, this study has completed enrollments, and final visits are expected by mid-2022. THE FOLLOW STUDY IS INVESTIGATIONAL USE OF UPPER AIRWAY STIMULATION THE INDICATION IS NOT CURRENTLY FDA APPROVED Effects of Hypoglossal Nerve Stimulation on Cognition and Language in Down Syndrome and OSA This is a prospective, single-arm study conducted in fifty-seven (57) adolescents and young adults (10-21 years of age), with Down syndrome, moderate to severe sleep apnea, and post-adenotonsillectomy, for 12 months after undergoing implant of the Upper Airway Stimulation (UAS) System. The aim of the study is to evaluate objective changes in cognition and expressive language after implant and therapy with the UAS System. Prior to the Cognition and Language study, a feasibility study of hypoglossal nerve stimulation in children with Down syndrome and moderate to severe obstructive sleep apnea, post-adenotonsillectomy, was initiated. This study included 42 adolescents and young adults (10-21 years of age) and focused on the safety of HNS in this population. In addition, efficacy was evaluated at 12 months post-implant. While initial results of this study (primarily safety) have been published, results related to 1 year follow-up are being prepared for publication. 6 PATIENT SELECTION & EVALUATION HYPOGLOSSAL NERVE THERAPY CARE PATHWAY FIGURE 3 INDICATIONS The first line therapy for patients with moderate to severe OSA remains CPAP [41] or alternative positive airway pressure (PAP) therapies, bilevel or auto-titrating. The efficacy of this therapy relies on the commitment of the patient to consistent use of this oft-perceived cumbersome treatment. Long term adherence with PAP therapy varies between 40-60% [42], despite a variety of strategies designed to mitigate the challenges. These include cognitive behavioral therapy (CBT) [43], education, motivational enhancement therapy (MET) [44-46], remote monitoring, and telemedicine [47], all with varying improvement in adherence. When confronted with a situation where a patient has not been successful or wishes to discontinue PAP therapy, other options should be presented for exploration, including oral appliances (mandibular advancement devices) [48], surgical procedures (otolaryngologic and skeletal) [49, 50], and hypoglossal nerve stimulation [51]. Hypoglossal nerve stimulation is a therapeutic option for patients who are intolerant of CPAP or in whom CPAP may not be effective (Figure 3). Stimulation of the hypoglossal nerve results in anterior movement of the tongue often with palatal coupling, hence opening the airway. This is a “dynamic” therapy as opposed to the other “static” surgical therapies previously available. The indicated criteria for surgical implant of a hypoglossal nerve stimulator include[52]: • • • • • Age > 18-21yrs with previous adenoidectomy and/or tonsillectomy Age > 22yrs No concentric collapse Demonstrate failure or intolerance to PAP therapy, Moderate to severe obstructive sleep apnea - AHI between 15 to 65/hr with < 25% central and mixed apneas with absence of a complete concentric collapse at the palatal level on drug induced sedation endoscopy (DISE). PAP failure is defined as an inability to eliminate OSA - AHI of greater than 15 despite PAP usage, and PAP intolerance is defined as: (1) Inability to use PAP (greater than 5 nights per week of usage; usage defined as greater than 4 hours of use per night), or (2) Unwillingness to use PAP (for example, a patient returns the PAP system after attempting to use it) [52] 7 BMI ≥ 32 is considered a precaution [52], not a contraindication, and is dependent on many other variables as to whether or not a patient is suitable for HNS therapy [53]. It is recommended that a prior auth approval is submitted since denial based on BMI can occur. DIAGNOSTIC TESTING Establishing the diagnosis of OSA requires specialized testing to measure the number of abnormal obstructive events during sleep, including an accurate AHI to predict responsiveness to non-PAP treatment modalities. Sleep testing is necessary to rule out other types of sleep disordered breathing such as central sleep apnea, mixed or complex sleep apnea, or hypoventilation, and provides an assessment of the severity of disease, as well as its impact on the sleep architecture and gas exchange parameters. Additionally, it can identify other abnormalities of sleep that can impact patients’ symptom burden such as movement disorders and parasomnias. Ideally, a recent sleep study (within the past year) is recommended to confirm the severity and to characterize the apneas (<25% central and mixed apneas). Polysomnography (PSG) or in-laboratory sleep study measures several parameters during sleep including electroencephalography, electromyography, and several respiratory and gas exchange parameters. PSG remains the reference standard for the diagnosis of OSA and the quantification of respiratory events and provides the most sensitive testing modality for the detection of central respiratory events. PSG has limitations that include relatively high cost and patient burden involved with sleeping in a foreign environment. Over the past three decades, several technologies were developed to perform sleep testing in the home setting. These technologies have evolved to include accurate measures of respiratory effort, airflow, and gas exchange during sleep making the diagnosis of OSA more reliable. Currently, home sleep apnea testing (HSAT) devices are accepted for the diagnosis of OSA as part of a comprehensive evaluation that includes assessment of patients’ symptoms, sleep pattern, and comorbidities. HSAT has several limitations including the absence of measures of sleep or movements, and its limited ability to detect and quantify central respiratory events, with the exception of one technology which has an indication for central sleep apnea. Sleep can now be measures with both HSAT using airflow; for example, Ensodata recently received FDA approval to determine sleep duration using airflow. Since HNS is most effective in patients with limited central sleep apneas, this latter limitation is particularly relevant when considering treatment options. HSAT can be an effective tool to establish the diagnosis of OSA in patients with high pretest probability. However, given that some HSAT devices do not measure sleep and can underestimate the AHI[54], they are less reliable for ruling out mild OSA (have lower negative predictive value) than the PSG. Importantly, and given this underestimation of AHI, caution is required before excluding treatment modalities such HNS in patients who have an AHI in the mild range (5-15) on HSAT that do not measure sleep. Recent advancements in artificial intelligence have demonstrated the ability to determine sleep time based on airflow via nasal transducer alone. Other limitations of HSAT include their lower reliability in patients with comorbidities such as heart failure; and their less established accuracy for the detection of central sleep apnea[55]. Relatively newer technologies utilizing peripheral arterial tonometry or photoplethysmography have demonstrated ability to not only determine AHI but also sleep onset, total sleep time and sleep architecture and have been validated against the gold stand in laboratory polysomnography. A few of these technologies (WatchPAT and SleepImage) have been validated to detect central apnea as well. The American Academy of Sleep Medicine (AASM) has provided useful guidelines for the utilization of HSAT that should be considered when incorporating HSAT in the decision tree for an HNS program. Of relevance is that diagnosis, assessment of treatment efficacy, and treatment decisions must not be based solely on automatically scored HSAT data, and the requirement of raw data from the HSAT device be reviewed and interpreted by a sleep specialist[55]. WEIGHT MANAGEMENT & BMI The association between weight and obstructive sleep apnea is bidirectional. Multiple studies have demonstrated the association of BMI with increased prevalence and severity of OSA [56-58]. In addition, multiple studies have 8 Commented [AR1]: Sleep can now be measures with both HSAT using airflow (ensodata recently got FDA approval to determine sleep duration using airflow; all PAT signal based HSATs can determine sleep Commented [AR2]: I think we need to clarify – HSAT that use airflow vs. HSATs that use Peripheral arterial tonometry to determine events; all airflow based HSATs can detect central apneas; PAT signal based - sleepimage and watchpat are the two that can detect central apneas Commented [AR3]: Incorrect Commented [AR4]: They can underestimate and overestimate Commented [AR5]: This can stay; demonstrated that the metabolic changes which occur, including changes in neuroendocrine secretion of leptin and ghrelin in patients with untreated OSA are associated with increasing BMI [59-61]. Untreated OSA is highly associated with metabolic syndrome and contributes to both metabolic dysregulation and systemic inflammation [62]. The AACE/ACE guideline recommends that all overweight and obese patients should be evaluated for OSA during medical history and physical exam [63]. Weight loss has been recommended in all patients with OSA with elevated BMI, and per the AASM Clinical Guidelines and the American Thoracic Society Guidelines, weight loss should be recommended for all overweight OSA patients[64, 65]. However, due to the low overall success and cure rate of dietary approaches for weight loss, it is recommended that a primary treatment for OSA be used in addition to weight loss [64]. Bariatric surgery is recommended as an adjunctive treatment for patients who have both OSA and other indications for surgery[64]; however, it has been noted that a significant number of patients will have persistent OSA after surgery [66-68]. Studies of gastric banding have shown that although improvement of AHI may be noted after weight loss, PAP therapy is more effective in AHI reduction than surgery alone [44]. Surprisingly, data suggest that although treatment of OSA would be expected to reduce the metabolic dysregulation associated with weight gain, patients with OSA who have been treated with PAP therapy have been noted to have a mild but statistically significant increase in weight [69]. As such, the understanding of the relationship between OSA and subsequent weight loss is not well understood. The use of hypoglossal nerve stimulators in patients with obstructive sleep apnea has been approved for patients who are overweight or have Class 1 obesity with BMI < 35 kg/m2 [70]. Surgical evaluation is recommended for all patients who have intolerance to PAP therapy or persistent inadequate PAP adherence due to pressure-related side effects [51]. Evaluation of the success rates of upper airway surgeries, including HNS therapy, on patients with elevated BMI, indicates that HNS is more effective in reduction of AHI and has more predictable response rates than anatomy altering airway surgery in patients with BMI index < 35 [39]. Additionally, data suggest that HNS surgery may have lower postoperative complication rates than classic upper airway surgery [39, 71]. SLEEP CO-MORBID CONDITIONS There is a growing body of evidence that psychosocial variables have a significant ability to predict the outcome of medical treatment procedures. Psychologists can provide a valuable role in assessment and screening of patients who are candidates for these interventions, especially elective, invasive procedures. Psychological evaluations are used to help assist physician decision-making, enhance patient awareness, and improve treatment planning for pre- and postsurgery in numerous areas, including bariatric surgery, spinal cord stimulator implants and organ transplants. Co-morbid insomnia and sleep apnea (COMISA) has been described in 39-58% of OSA patients and has been found to negatively impact acceptance and use of PAP therapy [72].. Initial reports suggest that untreated insomnia disorder may be a relative contraindication to UAS therapy due to potential decreased therapy usage [73, 74] In particular, the nerve stimulation may worsen or even lead to insomnia due to arousals that might be produced by tongue movements. There also is conflicting data suggesting that UAS can also improve insomnia as measured by the insomnia severity index [75]. Regardless, due to this potential interaction, it is recommended to screen for insomnia during UAS patient selection and treat the insomnia with cognitive behavioral therapy for insomnia (CBT-I), along with other medication management as deemed appropriate, prior to the procedure [76]. Another important aspect of pre-surgical screening is that when problematic psychosocial factors are identified, the treatment team and patient can be alerted and make appropriate recommendations to enhance surgical outcomes. Additional aspects of the pre-surgical psychological screening that can be beneficial for UAS candidates include: • • • Providing psychoeducation to the patient regarding realistic post op expectations Recommend pharmacological interventions to address potential post-surgical stumbling blocks (i.e., severe depression, anxiety, or substance use concerns) Identification of rare contraindications for implants (i.e., psychotic disorders, suicidal ideation) 9 In summary, recommendations for patients under consideration for UAS therapy include screening for insomnia disorder prior to UAS implementation and initiation of insomnia treatment, specifically focusing on CBT-I prior to UAS surgery or activation. Future research should continue to explore the impact of insomnia disorder and treatment on UAS therapy adherence, as well as identification of psychosocial risk factors that may lead to difficulties with adherence and use of UAS. There may be specific settings with UAS stimulation that maybe better suited for patients with insomnia, future research in this area is needed. PATIENT SELECTION AND RISK STRATIFICATION As patients are evaluated for HNS therapy, key medical and surgical factors play a role in the thoughtful assessment, management, and success for the patient. In addition to medical risk stratification, there is also surgical risk stratification to take into consideration. Factors such as co-morbid sleep conditions, co-morbid higher risk chronic conditions such as diabetes and heart failure, and anatomical presentation all play an important role in the management of care. Further research is needed to appropriately quantify and identify key objective and subjective risk factors that identify patients as low, moderate, or high-risk candidates for HNS therapy to manage patient and physician expectations appropriately. PATIENT EDUCATION & EXPECTATION MANAGEMENT Memory for patient medical information is often poor and inaccurate, especially if the patient is elderly or anxious [77]. In addition, recent studies have demonstrated that patients with OSA have trouble recalling memories and details [78, 79]. Despite varying levels of health literacy, low patient recall rates of information may negatively impact patient engagement in care and shared decision making with their care team [80]. There is growing literature that engaged and educated patients can lead to ‘improved effectiveness, efficiency, quality of care, health outcomes, and cost-effective health service utilization [81]. As patients undergo evaluation for HNS therapy, special attention to patient education needs and ongoing emphasis and reinforcement regarding the process and appropriate management of expectations is key to successfully handling frustrations that can naturally arise, both for the patient and the clinician care team. Through assessment of educational technology, patient’s learning style and understanding, involvement of the family members as needed and linking these strategies through patient education to the delivery of patient care, physicians and their care teams can optimize the use of patient education materials, either by creating their own and/or through materials provided by the manufacturer, such as the Inspire Sleep patient app. ENT CONSULTATION Patients enter the HNS clinical treatment pathway through various paths that include self-referred, sleep medicine partners, and other specialties. At this stage of care, it is critical that surgeons assess patients beyond the FDA indications and to manage patient expectations, particularly when the longitudinal care returns the patient back to their sleep medicine colleagues. 10 DRUG-INDUCED SLEEP ENDOSCOPY: DISE Drug-induced sleep endoscopy (DISE) represents one of the most compelling developments in the field of sleep surgery. Accurate determination of the level and pattern of airway collapse is crucial to surgical success in the treatment of CPAP-intolerant OSA patients [82] (Figure 4). As a diagnostic tool, DISE provides a dynamic, real-time assessment of the complex, three-dimensional interactions of key anatomic structures during conditions that closely resemble stage 2 sleep. It is this last point that sets DISE apart from previously used diagnostic tools including the Fujita classification, awake fiberoptic laryngoscopy, and the Mueller maneuver. Various pharmacologic agents have been used during DISE including propofol, midazolam, and dexmedetomidine. To address concerns about the comparability of drug-induced and natural sleep, PSG and genioglossus EMG studies have been performed [83-85]. Rabelo et al. showed no significant difference in AHI between propofol-induced and natural sleep but slightly greater oxygen desaturation and the lack of REM sleep in the propofol group [83]. The diminished muscle tone seen during drug-induced sleep is comparable with that seen during natural sleep. More recently, dexmedetomidine has been advocated for due to less potential for respiratory alteration; however, the additional monitoring time postprocedure among other confounders appears to have limited its general level of uptake for purposes of DISE[85]. Multiple studies have reported improved outcomes with DISE-guided Figure 4. Drug-induced sleep endoscopy treatment [86-90]. The absence of complete concentric palatal collapse during DISE is one of the critical parameters associated with successful application of HNS therapy [91]. While not a contraindication, Huyett et al. recently reported that the presence of complete lateral pharyngeal wall collapse during DISE is associated with poorer outcomes [92]. A retrospective study by Soares et al. found that the significant lateral oropharyngeal wall collapse or supraglottic collapse was associated with worse outcomes after soft tissue surgery to treat OSA [93]. In 2017, Huntley et al. reported improved success as well as a decrease in the number of patients undergoing multilevel soft tissue surgery when DISE was used to guide surgical planning [94]. Finally, the finding of increased airway dimensions with jaw thrust during DISE have been associated with increased likelihood of successful treatment with oral appliance therapy [95]. HNS with Inspire efficacy is highest when patients have an anteroposterior collapse pattern of the soft palate as opposed to a complete concentric collapse pattern of the soft palate, and with AHI and BMI values within certain thresholds [91]. It has also been demonstrated that patients with concentric collapse are more likely to have higher AHI and BMI [89, 96]. Despite many articles extolling the benefits of DISE, no clear consensus regarding its utility exists in the literature. Critics point to the exam’s subjective nature, variation in medication used, the lack of a standard grading scale, and variable application of the information obtained during the exam. Blumen et al. showed that treatment of all levels of obstruction identified during DISE failed to yield consistent improvement. Such findings could be due to poor procedure choice or the inability of available surgical options to adequately address certain findings. The authors also reported that failure to treat all areas of obstruction identified on DISE did not consistently result in poor outcomes [97]. A recent nonrandomized, prospective, multicenter trial by Pang et al showed that patients who underwent DISE had worse outcomes than those treated without DISE, perhaps owing to increased performance of nasal surgery in the no-DISE group. Both DISE technique and procedures performed based on findings were highly variable [98]. With nearly five hundred peer-reviewed articles published in the last five years, it is clear that interest in DISE as a tool in the sleep surgeon’s armamentarium remains at an all-time high in determining adjunctive OSA treatment options that include HNS therapy. Improved standardization of DISE technique and grading as well as how to best utilize the information gained is necessary to more clearly define the role of DISE in the management of CPAP-intolerant OSA patients. 11 PRE-SURGICAL PLANNING Initial pre-surgical planning must take into account incision planning with special attention to differences between men and women as well as the patient's occupation and hobbies. Incision Planning Incisions are preferentially planned on the right side to avoid any potential future conflict with cardiac devices. Two incisions are utilized, a 3-4cm submandibular incision and an approximate 5cm chest incision [76]. The submandibular incision runs parallel to the mandible halfway between the inferior border of the mandible and hyoid bone. The chest incision is planned to house the device, as well as allow access for the sensor lead placement. It is located at the second rib space beginning 3cm lateral to sternum. In men and women, the submandibular incision will heal with a visible but typically cosmetically acceptable scar. The chest incision may be visible in women depending on attire. If desired for cosmetic concerns, the chest dissection can proceed through an incision planned in a skin fold near the axilla [76]. Occupation and Hobbies Considerations There are very few activities that are incompatible with HNS, however a full history directed towards a patient’s occupation and hobbies should be taken to avoid issues. • • • • • Hunters and Recreational Shooters o Hunters and recreational shooters can generally receive HNS, with potential modifications to the procedure to allow for the gunstock to rest away from the device by a more medial position or a left sided implant. Hiking o Hikers who carry heavy backpacks can mark the location of the straps on their packs to aid in surgical planning. Skydiving o Skydiving is precaution with HNS as the sudden force applied to the area near the device with chute opening could damage the device . Deep sea-diving o The forces generated by diving below 10 meters (generator model 3024) or 30 meters (generator model 3028) or hyperbaric chambers could damage the device leads and should be avoided. Industrial Occupations o Rarely, workers in industrial fields may be subject to high levels of electromagnetic interference (EMI), which could interfere with implantable devices. Welding equipment, operating in certain modes, may generate an electromagnetic field strong enough to cause EMI and therefore should be avoided[99]. Strong magnets, transmitters, induction heaters, and power generators are also potential sources for EMI. HYPOGLOSSAL NERVE PROCEDURE 12 SURGICAL IMPLANT Currently, this 2-incision surgery [32] is performed as an outpatient procedure, either in a hospital or ambulatory surgical center, with similarly low post-operative complication rates [33] This procedure can range, on average, from 60-150 minutes, depending on the experience of the surgeon and staff [32]. Both incisions are typically on the patient’s right side (Figure 5), allowing the left chest wall to be available for possible cardiac pacemakers/defibrillators [76]. However, for patients who need a left sided implant, it can be done with minimal modification to the surgical technique [76]. Figure 5. Inspire Implant The first incision, approximately 1.5 inches in length is just below the right jaw line. Through this incision, the hypoglossal nerve is identified. Once the correct nerve is located, it is further dissected to separate the branches that lead to tongue protrusion from those that retract the tongue. The nerve is stimulated intraoperatively with EMG electrodes in the tongue to help differentiate the “inclusion” from the “exclusion” branches [76]. Once the surgeon is satisfied with the dissection, an electrode cuff is wrapped around the inclusion nerve branches and the electrode is then anchored to the digastric tendon. The second incision, around 2 inches in length, is made in the right anterior chest wall, located approximately 3 fingerbreadths below the mid-clavicle (Figure 6). A subcutaneous pocket is created for the generator/pacemaker and the fibers of the pectoral major muscle are spread to exposure the fascia of external intercostal muscles. Once the external intercostal muscles are identified, a small pocket between this and the internal intercostal muscle is created where the respiratory sense probe is situated. This probe contains a piezo-electric crystal that is pressure sensitive and can determine respiratory patterns based on chest wall pressure changes. The respiratory sense electrode is now anchored in place with non-absorbable suture. The free end of the stimulation electrode is tunneled under the neck skin and pulled into the upper chest incision. Both electrodes are then connected to the pulse generator, and the device is placed into the subcutaneous pocket and anchored in place with suture. Intraoperative testing is performed to observe for appropriate tongue motion as well as respiratory waveform from the sense electrode. If either result looks nonsatisfactory, the surgeon can immediately investigate the placement of either electrode and make adjustments. Once the surgeon is satisfied with the results, the device is turned back off and the incisions are closed in layered fashion. After surgery, patients typically are discharged home with analgesic pain management and /or appropriate antibiotics after an observational period in the recovery room [76]. Patients are followed up 7-10 days post-op for an incision check. Figure 6. Chest Wall Incision As patients are healing, surgical swelling is expected in addition to activity limitations such as over the head lifting or strenuous activity for at least two weeks [76]. ADVERSE EVENTS AND COMPLICATION MANAGEMENT Complications related to HNS implant surgery can be generally broken down into two broad categories: 13 1) intraoperative, and 2) postoperative. As noted in the STAR trial [36] , temporary tongue weakness (18%), post-op incision and device discomfort (51%), discomfort related to device stimulation (40%), and tongue abrasion (21%) were more common non-serious adverse events. More serious adverse events during the follow up period were much less common and included device revision (2%) and device-related infection (1%). Five year STAR follow up data[37] showed that 8 participants (6%) had a total of 9 device-related serious adverse events: revision due to discomfort (n=2), unfavorable tongue movement (n=1), insulation failure of respiratory sensing lead (n=4), and inadvertent cutting of the stimulation lead (n=1). A recent meta-analysis pooled data from 7 high-quality prospective studies found only 12 of 195 patients experienced 14 serious adverse events (6.1%) [100]. Peri and post-operative complications to be aware of include [76, 101]: • Bleeding o Typically, tunnel bleeding can be avoided by meticulous blunt dissection in a subplatysmal plane medial to the external jugular vein, but not so medial to encounter anterior jugular veins. If it occurs, it is often venous bleeding, which can be controlled with topical pressure. Rarely is neck exploration via additional neck incision necessary. • Pneumothorax o Often this is not recognized intra-operatively and can be avoided by meticulous blunt intercostal muscle dissection with limited blind tunneling. o If identified and asymptomatic, patients can be treated with oxygen and serial radiographic imaging. o If large, symptomatic or tension, chest tube drainage needs to be performed in collaboration with computed tomography (CT) or general surgery. • Infection • Hematoma o Surgical drainage (only for acute expanding hematoma) or device explantation (for abscess/severe infection) is rarely necessary. • Neuropraxia o Minor tongue weakness is not uncommon after surgery; in general, it almost always resolves in less than two weeks post-procedure. Lower lip weakness is most commonly related to cervical branch (facial nerve) pseudo-palsy or traction injury. Approaching the submandibular gland from a medial/inferior direction or identifying the anterior belly of the digastric muscle early in the course of dissection can limit risks to the marginal mandibular branch of the facial nerve • Twiddler’s syndrome o Twiddler’s syndrome, as the name implies, involves patients consciously or subconsciously flipping or twisting the device and altering its position in the chest, often to the point of damaging one or both lead wires requiring explant and revision [102]. Hypoglossal Nerve Stimulation surgery has a demonstrated safety profile as published across many studies [36, 37, 103]. ADHERE reported on safety outcomes in 301 patients showing 97% of procedures completed without report of an adverse outcome. Serious adverse outcomes were rare such as need for revision (1%), tongue weakness (1%), speech or swallow complaints (1%), and pain related to the device (2%) [39] (Figure 7, 8). Figure 7. ADHERE Registry Figure 8. ADHERE Registry, Patient Experience Report 14 THERAPY OPTIMIZATION To date, only two papers have fully addressed standardization of post-implant care management for patients with Inspire [104, 105] Soose et al. reviewed the most up to date, standardized care pathway guidelines [105]. The guidelines reviewed here provide additional considerations to the patient acclimation phase based on ongoing learnings since the article’s original publication. ACTIVATION AND ACCLIMATION From the acute stage of implant to activation, there is a waiting period of one month to allow the healing of the nervecuff interface and incisions for most patients. Approximately one month after implant, the patient returns to the clinic to have the device activated. Utilizing the programmer, the physician, advanced practitioner, sleep tech, or navigator, to turn on the device (is the sleep tech/navigator standard of care?). At this visit, the patient is given instructions to slowly step-up their stimulation level once per week. The step-up process is called the acclimation phase and lasts approximately three months. Early monitoring of adherence and subjective benefit during the acclimation phase is critical to ensuring patient success with the therapy. In the acclimation phase, the patient self-titrates to adapt to the sensation of stimulation and assess the subjective experience with the therapy. The desired outcome is at the end of this acclimation phase, the patient has self-titrated to a level that is close to their therapeutic amplitude setting. During this 3-month period, it is important to monitor patients and check-in at least twice to see how patients are managing the therapy to assess, comfort, adherence and subjective benefit. The first check-in is generally recommended to occur one month (we usually 1-2 weeks) after the Activation visit and can be completed either as a phone call or telemedicine visit, dependent on the care model and staffing of the managing physician office. If it is determined during this quick phone call or telemedicine visit that the patient experience is sub-optimal due to factors such as discomfort with the therapy, it is recommended that the patient is scheduled for an in-office visit to download the objective adherence to assess patient’s therapy utilization. There are a variety of treatment options available to optimize the therapy that include alternative programming settings and pharmacological interventions to enhance the patient experience with the therapy. It is worth noting that the acclimation period could take much longer than 3 months for some patients; in rare cases, this period can last as long as 6-9 months. However, once the acclimation period has concluded, the patient should be assessed to determine efficacy, either through an in-lab PSG or HST. Multiple factors impact the decision on test type that may include physician assessment, patient preference, adequate staffing, and the overall pandemic situation and baseline testing?. Whether it is an in-lab PSG or HST, it is recommended that the patient have a follow-up visit in the clinic to review sleep study results, verify adherence, and program final settings for each patient. At this visit, each patient can be appropriately triaged into either long-term follow-up care known as the green care pathway or continue with adjustments and/or medical management to optimize AHI reduction, increase adherence or improve subjective benefit currently known as the yellow care pathway. 15 For patients requiring additional intervention to optimize outcomes, typically the first step begins with simple, officebased adjustments in the clinic. For patients with a high residual AHI, awake endoscopy may be an appropriate intervention for the patient. Awake endoscopy is used to assess the impact of different settings on airway opening as well as to assess improving airway potential utilizing nasal vs. oral breathing, neck flexion and a jaw thrust maneuver, both with and without stimulation. If the awake endoscopy does not reveal improvements through electrode configuration or identify any airway deficiencies that can be improved, a second titration advanced PSG with technical support from Inspire on site to troubleshoot and evaluate advanced programming and sensor settings. It is important to remember that for some patients, HNS therapy is not a singular solution. Other combination therapy such as positional or oral appliances should be considered and can be utilized to individualize and optimize the patient outcomes. The goal of the care pathway is to ensure the best possible patient outcomes through a consistent, evidence-based algorithm that is dynamic as ongoing research continues to determine clinical and anatomical factors that enhance the patient success with HNS therapy. INSOMNIA POST-IMPLANTATION Given the high prevalence of COMISA (comorbid insomnia and sleep apnea), many individuals pursuing OSA treatment such as PAP or UAS (Upper airway stimulation) therapy may experience insomnia and associated hyperarousal and hypersensitivity to treatment. Individuals undergoing UAS therapy may experience negative psychological reactions to device implantation, activation, or use leading to adverse consequences. While not reported to be painful, the subjective experience of UAS stimulations may be unfamiliar, uncomfortable, or anxiety provoking to some. For some patients, this sensation alone may sometimes be incompatible with the relaxed psychological state for optimal sleep onset and maintenance. Although stimulation is