Medline ® Abstracts for References 77-85

BACKGROUND: Reduced upper airway muscle activity during sleep is fundamental to obstructive sleep apnea (OSA) pathogenesis. Hypoglossal nerve stimulation (HGNS) counteracts this problem, with potential to reduce OSA severity.

STUDY OBJECTIVES: To examine safety and efficacy of a novel HGNS system (HGNS, Apnex Medical, Inc.) in treating OSA.

PARTICIPANTS: Twenty-one patients, 67% male, age (mean±SD) 53.6±9.2 years, with moderate to severe OSA and unable to tolerate continuous positive airway pressure (CPAP).

DESIGN: Each participant underwent surgical implantation of the HGNS system in a prospective single-arm interventional trial. OSA severity was defined by apnea-hypopnea index (AHI) during in-laboratory polysomnography (PSG) at baseline and 3 and 6 months post-implant. Therapy compliance was assessed by nightly hours of use. Symptoms were assessed using the Epworth Sleepiness Scale (ESS), Functional Outcomes of Sleep Questionnaire (FOSQ), Calgary Sleep Apnea Quality of Life Index (SAQLI), and the Beck Depression Inventory (BDI).

RESULTS: HGNS was used on 89%±15% of nights (n = 21). On these nights, it was used for 5.8±1.6 h per night. Nineteen of 21 participants had baseline and 6-month PSGs. There was a significant improvement (all P<0.05) from baseline to 6 months in: AHI (43.1±17.5 to 19.5±16.7), ESS (12.1±4.7 to 8.1±4.4), FOSQ (14.4±2.0 to 16.7±2.2), SAQLI (3.2±1.0 to 4.9±1.3), and BDI (15.8±9.0 to 9.7±7.6). Two serious device-related adverse events occurred: an infection requiring device removal and a stimulation lead cuff dislodgement requiring replacement.

CONCLUSIONS: HGNS demonstrated favorable safety, efficacy, and compliance. Participants experienced a significant decrease in OSA severity and OSA-associated symptoms.

CLINICAL TRIAL INFORMATION: NAME: Australian Clinical Study of the Apnex Medical HGNS System to Treat Obstructive Sleep Apnea.

REGISTRATION NUMBER: NCT01186926. URL: http://clinicaltrials.gov/ct2/show/NCT01186926.

OBJECTIVE: To characterize the changes in the anteroposterior dimensions of both the retropalatal and retrolingual airway spaces of the pharynx and hyoid bone position during hypoglossal nerve stimulation under general anesthesia in subjects with obstructive sleep apnea.

STUDY DESIGN: Cross-sectional.

SETTING: Academic center.

SUBJECTS AND METHODS: Cross-table fluoroscopic images obtained during hypoglossal nerve stimulation were studied in 26 subjects enrolled in the Apnex Medical Hypoglossal Nerve Stimulation (HGNS) system feasibility trials. Changes in the anteroposterior dimensions (2-dimensional) of the retropalatal and retrolingual airway spaces and hyoid bone position were recorded. Measurements were estimated in millimeters and standardized to each subject's C3 vertebral height. Opening of the pharyngeal airspace was examined relative to body mass index.

RESULTS: During hypoglossal nerve stimulation, all subjects demonstrated anterior displacement ofthe tongue base on fluoroscopy. The average retrolingual airway opening was 0.71±0.23 C3 vertebral body heights (9±3 mm). Opening of the retropalatal airway with stimulation occurred in 65% (15/23) of subjects. When present, the average opening was 0.42±0.14 vertebral heights (5±3 mm). Anterior displacement of the hyoid occurred in 92% (23/25) of subjects. Retrolingual airway opening was independent of baseline body mass index.

CONCLUSION: Unilateral hypoglossal nerve stimulation results in anterior tongue base displacement and an increase in the anterior-posterior retrolingual airway dimensions of the pharynx, independent of body mass index. Opening of the retropalatal airway occurred in a majority of subjects and had a trend toward correlation with body mass index.

RATIONALE: Hypoglossal nerve stimulation (HGNS) recruits lingual muscles, reduces pharyngeal collapsibility, and treats sleep apnea.

OBJECTIVES: We hypothesized that graded increases in HGNS relieve pharyngeal obstruction progressively during sleep.

METHODS: Responses were examined in 30 patients with sleep apnea who were implanted with an HGNS system. Current (milliampere) was increased stepwise during non-REM sleep. Frequency and pulse width were fixed. At each current level, stimulation was applied on alternating breaths, and responses in maximal inspiratory airflow (V(I)max) and inspiratory airflow limitation (IFL) were assessed. Pharyngeal responses to HGNS were characterized by the current levels at which V(I)max first increased and peaked (flow capture and peak flow thresholds), and by the V(I)max increase from flow capture to peak (ΔV(I)max).

MEASUREMENTS AND MAIN RESULTS: HGNS produced linear increases in V(I)max from unstimulated levels at flow capture to peak flow thresholds (215±21 to 509±37 ml/s; mean±SE; P<0.001) with increasing current from 1.05±0.09 to 1.46±0.11 mA. V(I)max increased in all patients and IFL was abolished in 57% of patients (non-IFL subgroup). In the non-IFL compared with IFL subgroup, the flow response slope was greater (1241±199 vs. 674±166 ml/s/mA; P<0.05) and the stimulation amplitude at peak flow was lower (1.23±0.10 vs. 1.80±0.20 mA; P<0.05) without differences in peak flow.

CONCLUSIONS: HGNS produced marked dose-related increases in airflow without arousing patients from sleep. Increases in airflow were of sufficient magnitude to eliminate IFL in most patients and IFL and non-IFL subgroups achieved normal or near-normal levels of flow, suggesting potential HGNS efficacy across a broad range of sleep apnea severity.

OBJECTIVES/HYPOTHESIS: Previous feasibility studies have shown that electrical stimulation of the hypoglossal nerve can improve obstructive sleep apnea (OSA). The current study examined the safety and preliminary effectiveness of a second generation device, the Upper Airway Stimulation (UAS) system, and identified baseline predictors for therapy success.

STUDY DESIGN: Two consecutive open prospective studies.

METHODS: UAS systems were implanted in patients with moderate to severe OSA who failed or were intolerant of continuous positive airway pressure (CPAP). The study was conducted in 2 parts. In part 1, patients were enrolled with broad selection criteria. Apnea hypopnea index (AHI) was collected using laboratory-based polysomnography at preimplant and postimplant visits. Epworth Sleepiness Scale (ESS) and Functional Outcomes of Sleep Questionnaire (FOSQ) were also collected. In part 2, patients were enrolled using selection criteria derived from the experience in part 1.

RESULTS: In part 1, 20 of 22 enrolled patients (two exited the study) were examined for factors predictive of therapy response. Responders had both a body mass index≤32 and AHI≤50 (P<.05) and did not have complete concentric palatal collapse. Part 2 patients (n = 8) were selected using responder criteria and showed an improvement on AHI from baseline, from 38.9±9.8 to 10.0±11.0 (P<.01) at 6 months postimplant. Both ESS and FOSQ improved significantly in part 1 and 2 subjects.

CONCLUSIONS: The current study has demonstrated that therapy with upper airway stimulation is safe and efficacious in a select group of patients with moderate to severe OSA who cannot or will not use CPAP as primary treatment.

Continuous positive airway pressure (CPAP) is an effective but cumbersome treatment for obstructive sleep apnoea (OSA). Noncompliant patients need alternative therapies. We studied a tongue neurostimulation approach: targeted hypoglossal neurostimulation (THN) therapy with the aura6000™System. A multi-contact electrode positioned around the main trunk of the twelfth nerve connected to an implanted pulse generator stimulates segments of the nerve, activating dilator muscles. The primary objective was to improve the polysomnographically determined apnoea/hypopnoea index (AHI) at 3 months, and maintain the improvement after 12 months of treatment. 13 out of 14 operated patients were successfully implanted. At 12 months, the AHI decreased from 45±18 to 21±17, a 53% reduction (p<0.001). The 4% oxygen desaturation index fell from 29±20 to 15±16 and the arousal index from 37±13 to 25±14, both p<0.001. The Epworth sleepiness scale decreased from 11±7 to 8±4 (p=0.09). THN was neither painful nor awakened patients, who all complied with therapy. There were two transient tongue paresis. The present study represents the longest study of any hypoglossal neurostimulation reported to date. We conclude that THN is safe and effective to treat OSA in patients not compliant with CPAP.

BACKGROUND: Obstructive sleep apnea is associated with considerable health risks. Although continuous positive airway pressure (CPAP) can mitigate these risks, effectiveness can be reduced by inadequate adherence to treatment. We evaluated the clinical safety and effectiveness of upper-airway stimulation at 12 months for the treatment of moderate-to-severe obstructive sleep apnea.

METHODS: Using a multicenter, prospective, single-group, cohort design, we surgically implanted an upper-airway stimulation device in patients with obstructive sleep apnea who had difficulty either accepting or adhering to CPAP therapy. The primary outcome measures were the apnea-hypopnea index (AHI; the number of apnea or hypopnea events per hour, with a score of≥15 indicating moderate-to-severe apnea) and the oxygen desaturation index (ODI; the number of times per hour of sleep that the blood oxygen level drops by≥4 percentage points from baseline). Secondary outcome measures were the Epworth Sleepiness Scale, the Functional Outcomes of Sleep Questionnaire (FOSQ), and the percentage of sleep time with the oxygen saturation less than 90%. Consecutive participants with a responsewere included in a randomized, controlled therapy-withdrawal trial.

RESULTS: The study included 126 participants; 83% were men. The mean age was 54.5 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 28.4. The median AHI score at 12 months decreased 68%, from 29.3 events per hour to 9.0 events per hour (P<0.001); the ODI score decreased 70%, from 25.4 events per hour to 7.4 events per hour (P<0.001). Secondary outcome measures showed a reduction in the effects of sleep apnea and improved quality of life. In the randomized phase, the mean AHI score did not differ significantly from the 12-month score in the nonrandomized phase among the 23 participants in the therapy-maintenance group (8.9 and 7.2 events per hour, respectively); the AHI score was significantly higher (indicating more severe apnea) among the 23 participants in the therapy-withdrawal group (25.8 vs. 7.6 events per hour, P<0.001). The ODI results followed a similar pattern. The rate of procedure-related serious adverse events was less than 2%.

CONCLUSIONS: In this uncontrolled cohort study, upper-airway stimulation led to significant improvements in objective and subjective measurements of the severity of obstructive sleep apnea. (Funded by Inspire Medical Systems; STAR ClinicalTrials.gov number, NCT01161420.).

OBJECTIVES/HYPOTHESIS: Poor adherence to continuous positive airway pressure treatment in obstructive sleep apnea (OSA) adversely affects the effectiveness of this therapy. This study aimed to systematically review the evidence regarding the efficacy and safety of hypoglossal nerve stimulation as an alternative therapy in the treatment of OSA.

DATA SOURCES: Scopus, PubMed, and Cochrane Library databases were searched (updated through September 5, 2014).

METHODS: Studies were included that evaluated the efficacy of hypoglossal nerve stimulation to treat OSA in adults with outcomes for apnea-hypopnea index (AHI), oxygen desaturation index (ODI), and effect on daytime sleepiness (Epworth Sleepiness Scale [ESS]). Tests for heterogeneity and subgroup analysis were performed.

RESULTS: Six prospective studies with 200 patients were included in this review. At 12 months, the pooled fixed effects analysis demonstrated statistically significant reductions in AHI, ODI, and ESS mean difference of -17.51 (95% CI: -20.69 to -14.34); -13.73 (95% CI: -16.87 to -10.58), and -4.42 (95% CI: -5.39 to -3.44), respectively. Similar significant reductions were observed at 3 and 6 months. Overall, the AHI was reduced between 50% and 57%, and the ODI was reduced between 48% and 52%. Despite using different hypoglossal nerve stimulators in each subgroup analysis, no significant heterogeneity was found in any of the comparisons, suggesting equivalent efficacy regardless of the system in use.

CONCLUSIONS: This review reveals that hypoglossal nerve stimulation therapy may be considered in selected patients with OSA who fail medical treatment. Further studies comparing hypoglossal nerve stimulation with conventional therapies are needed to definitively evaluate outcomes.

LEVEL OF EVIDENCE: NA Laryngoscope, 125:1254-1264, 2015.

OBJECTIVE: To determine the stability of improvement in polysomnographic measures of sleep disordered breathing, patient reported outcomes, the durability of hypoglossal nerve recruitment and safety at 18 months in the Stimulation Treatment for Apnea Reduction (STAR) trial participants.

DESIGN: Prospective multicenter single group trial with participants serving as their own controls.

SETTING: Twenty-two community and academic sleep medicine and otolaryngology practices.

MEASUREMENTS: Primary outcome measures were the apnea-hypopnea index (AHI) and the 4% oxygen desaturation index (ODI). Secondary outcome measures were the Epworth Sleepiness Scale (ESS), the Functional Outcomes of Sleep Questionnaire (FOSQ), and oxygen saturation percent time<90% during sleep. Stimulation level for each participant was collected at three predefined thresholds during awake testing. Procedure- and/or device-related adverse events were reviewed and coded by the Clinical Events Committee.

RESULTS: The median AHI was reduced by 67.4% from the baseline of 29.3 to 9.7/h at 18 mo. The median ODI was reduced by 67.5% from 25.4 to 8.6/h at 18 mo. The FOSQ and ESS improved significantly at 18 mo compared to baseline values. The functional threshold was unchanged from baseline at 18 mo. Two participants experienced a serious device-related adverse event requiring neurostimulator repositioning and fixation. No tongue weakness reported at 18 mo.

CONCLUSION: Upper airway stimulation via the hypoglossal nerve maintained a durable effect of improving airway stability during sleep and improved patient reported outcomes (Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire) without an increase of the stimulation thresholds or tongue injury at 18 mo of follow-up.

OBJECTIVE: To describe the 36-month clinical and polysomnography (PSG) outcomes in an obstructive sleep apnea (OSA) cohort treated with hypoglossal cranial nerve upper airway stimulation (UAS).

STUDY DESIGN: A multicenter prospective cohort study.

SETTING: Industry-supported multicenter academic and clinical setting.

SUBJECTS: Participants (n = 116) at 36 months from a cohort of 126 implanted participants.

METHODS: Participants were enrolled in a prospective phase III trial evaluating the efficacy of UAS for moderated to severe OSA. Prospective outcomes included apnea-hypopnea index, oxygen desaturation index, other PSG measures, self-reported measures of sleepiness, sleep-related quality of life, and snoring.

RESULTS: Of 126 enrolled participants, 116 (92%) completed 36-month follow-up evaluation per protocol; 98 participants additionally agreed to a voluntary 36-month PSG. Self-report daily device usage was 81%. In the PSG group, 74% met the a priori definition of success with the primary outcomes of apnea-hypopnea index, reduced from the median value of 28.2 events per hour at baseline to 8.7 and 6.2 at 12 and 36 months, respectively. Similarly, self-reported outcomes improved from baseline to 12 months and were maintained at 36 months. Soft or no snoring reported by bed partner increased from 17% at baseline to 80% at 36 months. Serious device-related adverse events were rare, with 1 elective device explantation from 12 to 36 months.

CONCLUSION: Long-term 3-year improvements in objective respiratory and subjective quality-of-life outcome measures are maintained. Adverse events are uncommon. UAS is a successful and appropriate long-term treatment for individuals with moderate to severe OSA.