Acute Upper Airway Responses to Hypoglossal Nerve Stimulation during Sleep in Obstructive Sleep Apnea

Abstract

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 (DV 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 6 21 to 509 6 37 ml/s; mean 6 SE; P , 0.001) with increasing current from 1.05 6 0.09 to 1.46 6 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 6 199 vs. 674 6 166 ml/s/mA; P , 0.05) and the stimulation amplitude at peak flow was lower (1.23 6 0.10 vs. 1.80 6 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.Keywords: obstructive sleep apnea; electrical hypoglossal nerve stimulation; pharynx; upper airway; titration Obstructive sleep apnea is characterized by recurrent episodes of upper airway obstruction during sleep (1). Airflow obstruction is thought to result from decreases in pharyngeal neuromuscular activity at sleep onset (2). These episodes lead to intermittent hypoxemia and recurrent arousals from sleep, accounting for the long-term neurocognitive (3, 4), metabolic (5), and cardiovascular (6) sequelae of this disorder. Nasal continuous positive airway pressure remains the mainstay of treatment for moderate to severe obstructive sleep apnea (7). Difficulties adhering to therapy can limit its effectiveness in the home setting (8, 9), and alternatives have been generally less effective in relieving upper airway obstruction during sleep (10-12).Hypoglossal nerve stimulation (HGNS) has been piloted as treatment for obstructive sleep apnea (13). Implantable HGNS systems have been developed to stimulate the hypoglossal nerve during inspiration, and recruit the lingual musculature, leading to decreases in pharyngeal collapsibility during sleep (14-17). Motor activity protrudes the tongue, and mitigates airflow obstruction during sleep (18,19)....

Effect of upper-airway stimulation for obstructive sleep apnoea on airway dimensions

“…This study is consistent with previous work that increasing stimulation amplitudes increases airflow, until reaching a plateau at higher amplitudes [13]. The previously reported plateau effect in flow is probably explained by the plateau of airway size at the retrolingual area, as seen in this study.…”

“…Therapeutic applications using neuromuscular electrical stimulation of the hypoglossal nerve and genioglossus muscle have been designed and evaluated as a potential alternative to positive airway pressure therapy and upper-airway surgical procedures [6][7][8][9][10][11][12][13]. The therapy consists of an implanted, programmable neurostimulation system, with a stimulation electrode around the protrusor branches of the right hypoglossal nerve and a respiration sensor placed in the right intercostal space to detect respiration [10,14,15].…”

Defining Phenotypic Causes of Obstructive Sleep Apnea. Identification of Novel Therapeutic Targets

“…Key pathophysiologic causes likely include (1) an anatomically compromised or collapsible upper airway (high passive critical closing pressure of the upper airway [Pcrit]) (6); (2) inadequate responsiveness of the upperairway dilator muscles during sleep (minimal increase in EMG activity to negative pharyngeal pressure) (7,8); (3) waking up prematurely to airway narrowing (a low respiratory arousal threshold) (9-13); and (4) having an oversensitive ventilatory control system (high loop gain) (13)(14)(15). Indeed, small physiologic studies have demonstrated interventions that lower Pcrit (16)(17)(18), increase the electrical activity to genioglossus (19,20), increase the arousal threshold (9), or lower loop gain (21,22) can reduce OSA severity. However, these important pathophysiologic traits have not been measured collectively in afflicted individuals.…”

A resource of potential drug targets and strategic decision‐making for obstructive sleep apnoea pharmacotherapy

“…Such an intervention may, therefore, improve the effectiveness of, and adherence to, other treatment mainstays, e.g., by reducing the absolute pressure required for effective nCPAP therapy, or the amount of jaw repositioning for effective oral appliance therapy. We also recognize that other strategies to increase tongue muscle tone via non-pharmacological means, e.g., surgically implanted upper airway stimulation devices 6–8 , may also prove effective for the treatment of OSA.…”