Design and rationale for the treating Obstructive Sleep Apnea using Targeted Hypoglossal Nerve Stimulation (OSPREY) trial.

Obstructive sleep apnea (OSA) affects nearly 1 billion people worldwide, including approximately 35 million US residents. OSA has detrimental cardiovascular and neurocognitive consequences. Positive airway pressure corrects sleep disordered breathing but is not always tolerated or used sufficiently. Oral appliances and surgery provide alternatives in select populations but are variably effective. Hypoglossal nerve stimulation can effectively treat obstructive sleep apnea. Targeted hypoglossal nerve stimulation (THN) is simpler than incumbent technology with no sensor and an easier, proximal electrode implantation. The third clinical study of THN, THN3, was the first randomized, controlled trial of hypoglossal nerve stimulation to demonstrate significant improvement of sleep disordered breathing in OSA. The present investigation reports the design of a novel trial of targeted stimulation to provide additional Level 1 evidence in moderate to severe obstructive apnea. OSPREY is a randomized, parallel-arm, 13-month trial wherein all subjects are implanted, 2/3 are activated at Month 1 ("Treatment") and 1/3 are activated at Month 7 ("Control"). The primary endpoint is the difference in apnea-hypopnea index response rates between Treatment and Control groups at Month 7. Secondary endpoints include quality of life and oximetry metrics. OSPREY follows an adaptive "Goldilocks" design which optimizes the number of subjects with the need for high-confidence results. A maximum of 150 subjects is allowed, at which study power of >95% is predicted. Interim analyses begin once 50 patients are randomized and recur after each 20 additional randomizations to detect early success or futility. OSPREY is a unique, efficient trial that should provide high-confidence confirmation of the safety and efficacy of targeted hypoglossal nerve stimulation for moderate to severe obstructive sleep apnea.

Transvenous phrenic nerve stimulation improves central sleep apnea, sleep quality, and quality of life regardless of prior positive airway pressure treatment.

STUDY OBJECTIVE: Positive airway pressure (PAP) therapy for central sleep apnea (CSA) is often poorly tolerated, ineffective, or contraindicated. Transvenous phrenic nerve stimulation (TPNS) offers an alternative, although its impact on previously PAP-treated patients with CSA has not been examined. METHODS: TPNS responses among PAP-naïve and prior PAP-treated patients from the remede® System Pivotal Trial were assessed. Of 151, 56 (37%) used PAP therapy before enrolling in the trial. Patients were implanted with a TPNS device and randomized to either active or deferred (control) therapy for 6 months before therapy activation. Apnea-hypopnea index (AHI) and patient-reported outcomes (PRO) were assessed at baseline, and 6 and 12 months following active therapy. RESULTS: Patients had moderate-severe CSA at baseline, which was of greater severity and more symptomatic in the PAP-treated vs. PAP-naïve group (median AHI 52/h vs. 38, central apnea index (CAI) 32/h vs. 18, Epworth Sleepiness Scale 13 vs. 10, fatigue severity scale 5.2 vs. 4.5). Twelve months of TPNS decreased AHI to <20/h and CAI to ≤2/h. Both groups showed reductions in daytime sleepiness and fatigue, improved well-being by patient global assessment, and high therapeutic acceptance with 98% and 94% of PAP-treated and PAP-naïve patients indicating they would undergo the implant again. Stimulation produced discomfort in approximately one-third of patients, yet <5% of prior PAP-treated participants discontinued therapy. CONCLUSION: Polysomnographic and clinical responses to TPNS were comparable in PAP-naïve and prior PAP-treated CSA patients. TPNS is a viable therapy across a broad spectrum of CSA patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01816776; March 22, 2013.

Leptin receptor expression in the dorsomedial hypothalamus stimulates breathing during NREM sleep in db/db mice.

STUDY OBJECTIVES: Obesity leads to obstructive sleep apnea (OSA), which is recurrent upper airway obstruction during sleep, and obesity hypoventilation syndrome (OHS), hypoventilation during sleep resulting in daytime hypercapnia. Impaired leptin signaling in the brain was implicated in both conditions, but mechanisms are unknown. We have previously shown that leptin stimulates breathing and treats OSA and OHS in leptin-deficient ob/ob mice and leptin-resistant diet-induced obese mice and that leptin's respiratory effects may occur in the dorsomedial hypothalamus (DMH). We hypothesized that leptin receptor LepRb-deficient db/db mice have obesity hypoventilation and that restoration of leptin signaling in the DMH will increase ventilation during sleep in these animals. METHODS: We measured arterial blood gas in unanesthetized awake db/db mice. We subsequently infected these animals with Ad-LepRb or control Ad-mCherry virus into the DMH and measured ventilation during sleep as well as CO2 production after intracerebroventricular (ICV) infusions of phosphate-buffered saline or leptin. RESULTS: Awake db/db mice had elevated CO2 levels in the arterial blood. Ad-LepRb infection resulted in LepRb expression in the DMH neurons in a similar fashion to wildtype mice. In LepRb-DMH db/db mice, ICV leptin shortened REM sleep and increased inspiratory flow, tidal volume, and minute ventilation during NREM sleep without any effect on the quality of NREM sleep or CO2 production. Leptin had no effect on upper airway obstruction in these animals. CONCLUSION: Leptin stimulates breathing and treats obesity hypoventilation acting on LepRb-positive neurons in the DMH.

Ansa Cervicalis Stimulation: A New Direction in Neurostimulation for OSA.

BACKGROUND: Hypoglossal nerve stimulation (HNS) is an alternative treatment option for patients with OSA unable to tolerate positive airway pressure but implant criteria limit treatment candidacy. Previous research indicates that caudal tracheal traction plays an important role in stabilizing upper airway patency. RESEARCH QUESTION: Does contraction of the sternothyroid muscle with ansa cervicalis stimulation (ACS), which pulls the pharynx caudally via thyroid cartilage insertions, increase maximum inspiratory airflow (VImax)? STUDY DESIGN AND METHODS: Hook-wire percutaneous electrodes were used to stimulate the medial branch of the right hypoglossal nerve and right branch of the ansa cervicalis innervating the sternothyroid muscle during propofol sedation. VImax was assessed during flow-limited inspiration with a pneumotachometer. RESULTS: Eight participants with OSA were studied using ACS with and without HNS. Compared with baseline, the mean VImax increase with isolated ACS was 298%, or 473 mL/s (95% CI, 407-539). Isolated HNS increased mean VImax from baseline by 285%, or 260 mL/s (95% CI, 216-303). Adding ACS to HNS during flow-limited inspiration increased mean VImax by 151%, or 205 mL/s (95% CI, 174-236) over isolated HNS. Stimulation was significantly associated with increase in VImax in both experiments (P < .001). INTERPRETATION: ACS independently increased VImax during propofol sedation and drove further increases in VImax when combined with HNS. The branch of the ansa cervicalis innervating the sternothyroid muscle is easily accessed. Confirmation of the ansa cervicalis as a viable neurostimulation target may enable caudal pharyngeal traction as a novel respiratory neurostimulation strategy for treating OSA.

Ultrasound Localization and Percutaneous Electrical Stimulation of the Hypoglossal Nerve and Ansa Cervicalis.

OBJECTIVE: Hypoglossal nerve stimulation for obstructive sleep apnea (OSA) can be effective for appropriately selected patients, but current patient selection criteria are complex and still result in a proportion of nonresponders. Ansa cervicalis stimulation of the infrahyoid cervical strap muscles has recently been proposed as a new form of respiratory neurostimulation (RNS) therapy for OSA treatment. We hypothesized that percutaneous stimulation of both nerves in humans with temporary electrodes would make testing of the physiologic response to different RNS strategies possible. STUDY DESIGN: Nonrandomized acute physiology study. SETTING: Tertiary care hospital. METHODS: Fifteen participants with OSA underwent ultrasonography and placement of percutaneous electrodes proximal to the medial division of the hypoglossal nerve and the branch of the ansa cervicalis innervating the sternothyroid muscle (ACST). Procedural success was documented in each participant, as were any failures or procedural complication. RESULTS: The hypoglossal nerve was successfully localized in 15 of 15 (100%) participants and successfully stimulated in 13 of 15 (86.7%). The ACST was successfully localized in 15 of 15 (100%) participants and successfully stimulated in 14 of 15 (93.3%). Stimulation failure of the hypoglossal nerve was due to suboptimal electrode placement in 1 participant and electrode displacement in the other 2 cases. No complications occurred. CONCLUSIONS: The hypoglossal nerve and ACST can be safely stimulated via percutaneous electrode placement. Larger trials of percutaneous stimulation may help to identify responders to different RNS therapies for OSA with temporary or permanent percutaneous electrodes. Techniques for electrode design, nerve localization, and electrode placement are described.

Novel phrenic nerve stimulator treats Cheyne-Stokes respiration: polysomnographic insights.

None: A symptomatic patient with atrial fibrillation and Cheyne-Stokes respiration (CSR) was implanted with a transvenous phrenic nerve stimulation (TPNS) device-the remede System-that is indicated for adult patients with moderate to severe central sleep apnea. Sleep recordings demonstrated that TPNS eliminated periodic breathing by activating the diaphragm and stabilizing respiratory patterns. These recordings of preprogrammed periods on versus off TPNS illustrate prompt (1) stabilization of tidal airflow, respiratory effort, and oxygenation as stimulation amplitude increased stepwise and (2) recurrence of CSR immediately after TPNS deactivated. Despite differences in respiratory patterns, minute ventilation was comparable during periods on and off TPNS. These findings suggest that diaphragmatic pacing entrains ventilation without disrupting sleep, accounting for observed improvements in periodic breathing, gas exchange, sleep architecture, and quality of life. Effective means to relieve CSR could potentially mitigate nocturnal cardiovascular stress and disease progression.

Neurostimulation Treatment of OSA.

Over the past 30 years, hypoglossal nerve stimulation has moved through a development pathway to become a viable treatment modality for patients with OSA. Initial pilot studies in animals and humans laid the conceptual foundation for this approach, leading to the development of fully implantable stimulating systems for therapeutic purposes. These devices were then shown to be both safe and efficacious in feasibility studies. One such closed-loop stimulating device was found to be effective in treating a limited spectrum of apneic patients and is currently approved by the US Food and Drug Administration for this purpose. Another open-loop stimulating system is currently being rigorously tested in a pivotal trial. Collectively, clinical trials of hypoglossal nerve stimulating systems have yielded important insights that can help optimize therapeutic responses to hypoglossal nerve stimulation. These insights include specific patient selection criteria and methods for delivering stimulation to specific portions of the hypoglossal nerve and/or genioglossus muscle. New approaches for activating efferent and afferent motor pathways are currently in early-stage laboratory development and hold some long-term promise as a novel therapy.

Optogenetic identification of hypothalamic orexin neuron projections to paraventricular spinally projecting neurons.

Orexin neurons, and activation of orexin receptors, are generally thought to be sympathoexcitatory; however, the functional connectivity between orexin neurons and a likely sympathetic target, the hypothalamic spinally projecting neurons (SPNs) in the paraventricular nucleus of the hypothalamus (PVN) has not been established. To test the hypothesis that orexin neurons project directly to SPNs in the PVN, channelrhodopsin-2 (ChR2) was selectively expressed in orexin neurons to enable photoactivation of ChR2-expressing fibers while examining evoked postsynaptic currents in SPNs in rat hypothalamic slices. Selective photoactivation of orexin fibers elicited short-latency postsynaptic currents in all SPNs tested (n = 34). These light-triggered responses were heterogeneous, with a majority being excitatory glutamatergic responses (59%) and a minority of inhibitory GABAergic (35%) and mixed glutamatergic and GABAergic currents (6%). Both glutamatergic and GABAergic responses were present in the presence of tetrodotoxin and 4-aminopyridine, suggesting a monosynaptic connection between orexin neurons and SPNs. In addition to generating postsynaptic responses, photostimulation facilitated action potential firing in SPNs (current clamp configuration). Glutamatergic, but not GABAergic, postsynaptic currents were diminished by application of the orexin receptor antagonist almorexant, indicating orexin release facilitates glutamatergic neurotransmission in this pathway. This work identifies a neuronal circuit by which orexin neurons likely exert sympathoexcitatory control of cardiovascular function.NEW & NOTEWORTHY This is the first study to establish, using innovative optogenetic approaches in a transgenic rat model, that there are robust heterogeneous projections from orexin neurons to paraventricular spinally projecting neurons, including excitatory glutamatergic and inhibitory GABAergic neurotransmission. Endogenous orexin release modulates glutamatergic, but not GABAergic, neurotransmission in these pathways.

Direct projections from hypothalamic orexin neurons to brainstem cardiac vagal neurons.

Orexin neurons are known to augment the sympathetic control of cardiovascular function, however the role of orexin neurons in parasympathetic cardiac regulation remains unclear. To test the hypothesis that orexin neurons contribute to parasympathetic control we selectively expressed channelrhodopsin-2 (ChR2) in orexin neurons in orexin-Cre transgenic rats and examined postsynaptic currents in cardiac vagal neurons (CVNs) in the dorsal motor nucleus of the vagus (DMV). Simultaneous photostimulation and recording in ChR2-expressing orexin neurons in the lateral hypothalamus resulted in reliable action potential firing as well as large whole-cell currents suggesting a strong expression of ChR2 and reliable optogenetic excitation. Photostimulation of ChR2-expressing fibers in the DMV elicited short-latency (ranging from 3.2ms to 8.5ms) postsynaptic currents in 16 out of 44 CVNs tested. These responses were heterogeneous and included excitatory glutamatergic (63%) and inhibitory GABAergic (37%) postsynaptic currents. The results from this study suggest different sub-population of orexin neurons may exert diverse influences on brainstem CVNs and therefore may play distinct functional roles in parasympathetic control of the heart.

Hypoxia and hypercapnia inhibit hypothalamic orexin neurons in rats.

Evidence of impaired function of orexin neurons has been found in individuals with cardiorespiratory disorders, such as obstructive sleep apnea (OSA) and sudden infant death syndrome (SIDS), but the mechanisms responsible are unknown. Individuals with OSA and SIDS experience repetitive breathing cessations and/or rebreathing of expired air, resulting in hypoxia/hypercapnia (H/H). In this study, we examined the responses of fluorescently identified rat orexin neurons in the lateral hypothalamus to acute H/H to test if and how these neurons alter their activity and function during this challenge. Experiments were conducted in an in vitro slice preparation using voltage-clamp and current-clamp configurations. H/H (10 min) induced hyperpolarization, accompanied by rapid depression, and finally, cessation of firing activity in orexin neurons. Hypoxia alone had similar but less potent effects. H/H did not alter the frequency of inhibitory glycinergic postsynaptic currents. The frequency of GABAergic currents was diminished but only at 8-10 min of H/H. In contrast, the frequency of excitatory glutamatergic postsynaptic events was diminished as early as 2-4 min of H/H. In the presence of glutamatergic receptor blockers, the inhibitory effects of H/H on the firing activity and membrane potential of orexin neurons persisted but to a lesser extent. In conclusion, both direct alteration of postsynaptic membrane properties and diminished glutamatergic neurotransmission likely contribute to the inhibition of orexin neurons by H/H. These mechanisms could be responsible for the decreased function of orexin in individuals at risk for OSA and SIDS.

Localizing Effects of Leptin on Upper Airway and Respiratory Control during Sleep.

STUDY OBJECTIVES: Obesity hypoventilation and obstructive sleep apnea are common complications of obesity linked to defects in respiratory pump and upper airway neural control. Leptin-deficient ob/ob mice have impaired ventilatory control and inspiratory flow limitation during sleep, which are both reversed with leptin. We aimed to localize central nervous system (CNS) site(s) of leptin action on respiratory and upper airway neuroventilatory control. METHODS: We localized the effect of leptin to medulla versus hypothalamus by administering intracerbroventricular leptin (10 µg/2 µL) versus vehicle to the lateral (n = 14) versus fourth ventricle (n = 11) of ob/ob mice followed by polysomnographic recording. Analyses were stratified for effects on respiratory (nonflow-limited breaths) and upper airway (inspiratory flow limitation) functions. CNS loci were identified by (1) leptin-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation and (2) projections of respiratory and upper airway motoneurons with a retrograde transsynaptic tracer (pseudorabies virus). RESULTS: Both routes of leptin administration increased minute ventilation during nonflow-limited breathing in sleep. Phrenic motoneurons were synaptically coupled to the nucleus of the solitary tract, which also showed STAT3 phosphorylation, but not to the hypothalamus. Inspiratory flow limitation and obstructive hypopneas were attenuated by leptin administration to the lateral but not to the fourth cerebral ventricle. Upper airway motoneurons were synaptically coupled with the dorsomedial hypothalamus, which exhibited STAT3 phosphorylation. CONCLUSIONS: Leptin relieves upper airway obstruction in sleep apnea by activating the forebrain, possibly in the dorsomedial hypothalamus. In contrast, leptin upregulates ventilatory control through hindbrain sites of action, possibly in the nucleus of the solitary tract.

Electrical stimulation of the hypoglossal nerve: a potential therapy.

Obstructive sleep apnea is characterized by recurrent episodes of pharyngeal collapse, which result from a decrease in pharyngeal dilator muscle tone. The genioglossus is a major pharyngeal dilator that maintains airway patency during sleep. Early studies in animal and humans have demonstrated that electrical stimulation of this muscle reduces pharyngeal collapsibility, increases airflow, and mitigates obstructive sleep apnea. These findings impelled the development of fully implantable hypoglossal nerve stimulating systems (HGNS), for which feasibility trial results are now available. These pilot studies have confirmed that hypoglossal nerve stimulation can prevent pharyngeal collapse without arousing patients from sleep. Potentially, a substantial segment of the patient population with obstructive sleep apnea can be treated with this novel approach. Furthermore, the feasibility trial findings suggest that the therapeutic potential of HGNS can be optimized by selecting patients judiciously, titrating the stimulus intensity optimally, and characterizing the underlying function and anatomy of the pharynx. These strategies are currently being examined in ongoing pivotal trials of HGNS.

Acute upper airway responses to hypoglossal nerve stimulation during sleep in obstructive sleep apnea.

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.

Treating obstructive sleep apnea with hypoglossal nerve stimulation.

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.

Effects of sleep apnea on nocturnal free fatty acids in subjects with heart failure.

STUDY OBJECTIVES: Sleep apnea is common in patients with congestive heart failure, and may contribute to the progression of underlying heart disease. Cardiovascular and metabolic complications of sleep apnea have been attributed to intermittent hypoxia. Elevated free fatty acids (FFA) are also associated with the progression of metabolic, vascular, and cardiac dysfunction. The objective of this study was to determine the effect of intermittent hypoxia on FFA levels during sleep in patients with heart failure. DESIGN AND INTERVENTIONS: During sleep, frequent blood samples were examined for FFA in patients with stable heart failure (ejection fraction < 40%). In patients with severe sleep apnea (apnea-hypopnea index = 65.5 ± 9.1 events/h; average low SpO2 = 88.9%), FFA levels were compared to controls with milder sleep apnea (apnea-hypopnea index = 15.4 ± 3.7 events/h; average low SpO2 = 93.6%). In patients with severe sleep apnea, supplemental oxygen at 2-4 liters/min was administered on a subsequent night to eliminate hypoxemia. MEASUREMENTS AND RESULTS: Prior to sleep onset, controls and patients with severe apnea exhibited a similar FFA level. After sleep onset, patients with severe sleep apnea exhibited a marked and rapid increase in FFA relative to control subjects. This increase persisted throughout NREM and REM sleep exceeding serum FFA levels in control subjects by 0.134 mmol/L (P = 0.0038). Supplemental oxygen normalized the FFA profile without affecting sleep architecture or respiratory arousal frequency. CONCLUSION: In patients with heart failure, severe sleep apnea causes surges in nocturnal FFA that may contribute to the accelerated progression of underlying heart disease. Supplemental oxygen prevents the FFA elevation.

Electrical stimulation of the hypoglossal nerve in the treatment of obstructive sleep apnea.

Upper airway occlusion in obstructive sleep apnea has been attributed to a decline in pharyngeal neuromuscular activity occurring in a structurally narrowed airway. Surgical treatment focuses on the correction of anatomic abnormalities, but there is a potential role for activation of the upper airway musculature, especially with stimulation of the hypoglossal nerve and genioglossus muscle. We present evidence from research on upper airway neuromuscular electrical stimulation in animals and humans. We also present results from eight obstructive sleep apnea patients with a fully implanted system for hypoglossal nerve stimulation, demonstrating an improvement in upper airway collapsibility and obstructive sleep apnea severity. Future research, including optimization of device features and stimulation parameters as well as patient selection, is necessary to make hypoglossal nerve stimulation a viable alternative to positive airway pressure therapy and upper airway surgical procedures.

Interacting effects of genioglossus stimulation and mandibular advancement in sleep apnea.

Both mandibular advancement (MA) and stimulation of the genioglossus (GG) have been shown to improve upper airway patency, but neither one achieves the effect of continuous positive airway pressure (CPAP) treatment. In the present study we assessed the combined effect of MA and GG stimulation on the relaxed pharynx in patients with obstructive sleep apnea (OSA). We evaluated responses of upper airway pressure-flow relationships and endoscopically determined pharyngeal cross-sectional area to MA and electrical stimulation of the GG in 14 propofol-anesthetized OSA patients. Measurements were undertaken at multiple levels of CPAP, enabling calculation of the critical closing pressure (Pcrit), upstream resistance (Rus), and pharyngeal compliance. GG stimulation, MA, and the combination of both shifted the pressure:flow relationships toward higher flow levels, resulting in progressively lower Pcrit (from baseline of 2.9 +/- 2.2 to 0.9 +/- 2.5, -1.4 +/- 2.9, and -4.2 +/- 3.3 cmH(2)O, respectively), without significant change in Rus. DeltaPcrit during GG stimulation was significantly larger during MA than under baseline conditions (-2.8 +/- 1.4 vs. -2.0 +/- 1.4 cmH(2)O, P = 0.011). Combining the effect of GG stimulation with MA lowered Pcrit below 0 in all patients and restored pharyngeal patency to a level that enabled flow above the hypopnea level in 10/14 of the patients. Velopharyngeal compliance was not affected by either manipulation. We conclude that the combined effect of MA and GG stimulation is additive and may act in synergy, preventing substantial flow limitation of the relaxed pharynx in most OSA patients.

Upper airway response to electrical stimulation of the genioglossus in obstructive sleep apnea.

Contraction of the genioglossus (GG) has been shown to improve upper airway patency. In the present study, we evaluated responses in upper airway pressure-flow relationships during sleep to electrical stimulation (ES) of the GG in patients with obstructive sleep apnea. Five patients with chronically implanted hypoglossal nerve (HG) electrodes and nine patients with fine-wire electrodes inserted into the GG were studied. Airflow was measured at multiple levels of nasal pressure, and upper airway collapsibility was defined by the nasal pressure below which airflow ceased ["critical" pressure (Pcrit)]. ES shifted the pressure-flow relationships toward higher flow levels in all patients over the entire range of nasal pressure applied. Pcrit decreased similarly during both HG-ES and GG-ES (deltaPcrit was 3.98 +/- 2.31 and 3.18 +/- 1.70 cmH2O, respectively) without a significant change in upstream resistance. The site of collapse (velo- vs. oropharynx) did not influence the response to GG-ES. Moreover, ES-induced reductions in the apnea-hypopnea index of the HG-ES patients were associated with substantial decreases in Pcrit. Our findings imply that responses in apnea severity to HG-ES can be predicted by characterizing the patient's baseline pressure-flow relationships and response to GG-ES.