Jennifer H. Walsh

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.

Comparison of forearm blood flow responses to incremental handgrip and cycle ergometer exercise: Relative contribution of nitric oxide

The contribution of endothelium‐derived nitric oxide (NO) to exercise hyperaemia remains controversial. Disparate findings may, in part, be explained by different shear stress stimuli as a result of different types of exercise. We have directly compared forearm blood flow (FBF) responses to incremental handgrip and cycle ergometer exercise in 14 subjects (age ±s.e.m.) using a novel software system which calculates conduit artery blood flow continuously across the cardiac cycle by synchronising automated edge‐detection and wall tracking of high resolution B‐mode arterial ultrasound images and Doppler waveform envelope analysis. Monomethyl arginine (l‐NMMA) was infused during repeat bouts of each incremental exercise test to assess the contribution of NO to hyperaemic responses. During handgrip, mean FBF increased with workload (P < 0.01) whereas FBF decreased at lower cycle workloads (P < 0.05), before increasing at 120 W (P < 0.001). Differences in these patterns of mean FBF response to different exercise modalities were due to the influence of retrograde diastolic flow during cycling, which had a relatively larger impact on mean flows at lower workloads. Retrograde diastolic flow was negligible during handgrip. Although mean FBF was lower in response to cycling than handgrip exercise, the impact of l–NMMA was significant during the cycle modality only (P < 0.05), possibly reflecting the importance of an oscillatory antegrade/retrograde flow pattern on shear stress‐mediated release of NO from the endothelium. In conclusion, different types of exercise present different haemodynamic stimuli to the endothelium, which may result in differential effects of shear stress on the vasculature.

Evolution of changes in upper airway collapsibility during slow induction of anesthesia with propofol.

Background:Upper airway collapsibility is known to increase under anesthesia. This study assessed how this increase in collapsibility evolves during slow Propofol induction and how it relates to anesthesia-induced changes in upper airway muscle activity and conscious state. Methods:Nine healthy volunteers were studied. Anesthesia was induced with Propofol in a step-wise manner (effect-site concentration steps of 0.5 &mgr;g · ml−1 from 0 to 3 &mgr;g · ml−1 and thereafter to 4 &mgr;g · ml−1 and 6 &mgr;g · ml−1 [target-controlled infusion]). Airway patency was maintained with continuous positive airway pressure. Pharyngeal collapsibility was assessed at each concentration by measuring critical pressure. Intramuscular genioglossus electromyogram and anesthetic depth (bispectral index score) were monitored throughout. Loss of consciousness was defined as failure to respond to loud verbal command. Results:Loss of consciousness occurred at varying Propofol effect-site concentrations between 1.5 and 4.0 &mgr;g · ml−1. Initially genioglossus electromyographic activity was sustained with increases in Propofol concentration, increasing in some individuals. At or approaching loss of consciousness, it decreased, often abruptly, to minimal values with an accompanying increase in critical pressure. In most subjects, bispectral index score decreased alinearly with increasing Propofol concentration with greatest rate of change coinciding with loss of consciousness. Conclusions:Slow stepwise induction of Propofol anesthesia is associated with an alinear increase in upper airway collapsibility. Disproportionate decreases in genioglossus electromyogram activity and increases in pharyngeal critical closing pressure were observed proximate to loss of consciousness, suggesting that particular vulnerability exists after transition from conscious to unconscious sedation. Such changes may have parallels with upper airway behavior at sleep onset.

Evaluation of pharyngeal shape and size using anatomical optical coherence tomography in individuals with and without obstructive sleep apnoea

This study compared shape, size and length of the pharyngeal airway in individuals with and without obstructive sleep apnoea (OSA) using a novel endoscopic imaging technique, anatomical optical coherence tomography (aOCT). The study population comprised a preliminary study group of 20 OSA patients and a subsequent controlled study group of 10 OSA patients and 10 body mass index (BMI)‐, gender‐ and age‐matched control subjects without OSA. All subjects were scanned using aOCT while awake, supine and breathing quietly. Measurements of airway cross‐sectional area (CSA) and anteroposterior (A‐P) and lateral diameters were obtained from the hypo‐, oro‐ and velopharyngeal regions. A‐P : lateral diameter ratios were calculated to provide an index of regional airway shape. In all subjects, pharyngeal CSA was lowest in the velopharynx. Patients with OSA had a smaller velopharyngeal CSA than controls (maximum CSA 91 ± 40 versus 153 ± 84 mm2; P < 0.05) but comparable oro‐ (318 ± 80 versus 279 ± 129 mm2; P = 0.48) and hypopharyngeal CSA (250 ± 105 versus 303 ± 112 mm2; P = 0.36). In each pharyngeal region, the long axis of the airway was oriented in the lateral diameter. Airway shape was not different between the groups. Pharyngeal airway length was similar in both groups, although the OSA group had longer uvulae than the control group (16.8 ± 6.2 versus 11.2 ± 5.2 mm; P < 0.05). This study has shown that individuals with OSA have a smaller velopharyngeal CSA than BMI‐, gender‐ and age‐matched control volunteers, but comparable shape: a laterally oriented ellipse. These findings suggest that it is an abnormality in size rather than shape that is the more important anatomical predictor of OSA.

Hypoglossal nerve stimulation improves obstructive sleep apnea: 12-month outcomes

Reduced upper airway muscle activity during sleep is a key contributor to obstructive sleep apnea pathogenesis. Hypoglossal nerve stimulation activates upper airway dilator muscles, including the genioglossus, and has the potential to reduce obstructive sleep apnea severity. The objective of this study was to examine the safety, feasibility and efficacy of a novel hypoglossal nerve stimulation system (HGNS®; Apnex Medical, St Paul, MN, USA) in treating obstructive sleep apnea at 12 months following implantation. Thirty‐one subjects (35% female, age 52.4 ± 9.4 years) with moderate to severe obstructive sleep apnea and unable to tolerate positive airway pressure underwent surgical implantation and activation of the hypoglossal nerve stimulation system in a prospective single‐arm interventional trial. Primary outcomes were changes in obstructive sleep apnea severity (apnea–hypopnea index, from in‐laboratory polysomnogram) and sleep‐related quality of life [Functional Outcomes of Sleep Questionnaire (FOSQ)]. Hypoglossal nerve stimulation was used on 86 ± 16% of nights for 5.4 ± 1.4 h per night. There was a significant improvement (P < 0.001) from baseline to 12 months in apnea–hypopnea index (45.4 ± 17.5 to 25.3 ± 20.6 events h−1) and Functional Outcomes of Sleep Questionnaire score (14.2 ± 2.0 to 17.0 ± 2.4), as well as other polysomnogram and symptom measures. Outcomes were stable compared with 6 months following implantation. Three serious device‐related adverse events occurred: an infection requiring device removal; and two stimulation lead cuff dislodgements requiring replacement. There were no significant adverse events with onset later than 6 months following implantation. Hypoglossal nerve stimulation demonstrated favourable safety, feasibility and efficacy.

Effects of exercise training on conduit and resistance vessel function in treated and untreated hypercholesterolaemic subjects

AIMS Despite the importance of both lipid metabolism and physical activity to cardiovascular health, few studies have examined the effect of exercise training on vascular function in hypercholesterolaemic humans. METHODS AND RESULTS A randomized, cross-over design investigated the effect of 8 weeks of combined aerobic and resistance exercise training on conduit and resistance vessel function in 11 untreated subjects with hypercholesterolaemia and 11 subjects taking lipid-lowering medication. High-resolution vascular ultrasonography following forearm ischaemia and glyceryl trinitrate administration determined conduit vessel endothelium-dependent and independent function. Strain-gauge plethysmography, with intra-aerial infusions of acetylcholine, sodium nitroprusside and N(G)-monomethyl-L-arginine, determined resistance vessel function. Flow-mediated dilation and the forearm blood flow response to acetylcholine improved significantly following training in the treated subgroup (both P<0.05) but not the untreated, although the blood flow response to N(G)-monomethyl-L-arginine was augmented following training in the untreated subjects (P<0.05), indicating greater basal nitric oxide bioactivity. Training did not alter responsiveness to glyceryl trinitrate or sodium nitroprusside. CONCLUSIONS Combined aerobic and resistance training improves endothelium-dependent conduit and resistance vessel function in hypercholesterolaemic subjects taking lipid-lowering medications and basal nitric oxide bioactivity in untreated hypercholesterolaemic subjects. Exercise training may provide additional cardiovascular benefits for hypercholesterolaemic patients including those taking lipid-lowering medication.

Using Optical Coherence Tomography To Improve Diagnostic and Therapeutic Bronchoscopy

Flexible bronchoscopy is a common procedure that is used in both diagnostic and therapeutic settings but does not readily permit measurement of central airway dimensions. Anatomic optical coherence tomography (a OCT), a modification of conventional optical coherence tomography (OCT), is a novel light-based imaging tool with the capacity to measure the diameter and lumen area of the central airways accurately during bronchoscopy. This study describes the first clinical use of aOCT imaging in the lower airways in three individuals with common endobronchial pathologies. During bronchoscopy, a specialized fiberoptic probe was passed through the biopsy channel of a standard flexible bronchoscope to the site of airway pathology. Airway dimensions were measured from the generated cross-sectional images in three subjects, one with subglottic tracheal stenosis (subject 1), one with malignant left main bronchus (LMB) obstruction (subject 2), and another with severe tracheomalacia (subject 3). Measured dimensions included internal airway diameter, cross-sectional area, and, in subject 1, stenosis length. Tracheal stenosis dimensions, measured using aOCT imaging, correlated with chest CT scan findings and guided the choice of airway stent (subject 1). The airway beyond a malignant obstruction of the LMB, and beyond bronchoscopic view, could be imaged using aOCT, and the distal extent of obstructing tumor identified (subject 2). The severity of newly diagnosed tracheomalacia was able to be quantified using aOCT imaging (subject 3). aOCT imaging during bronchoscopy allows accurate real-time airway measurements and may assist bronchoscopic assessment.

Anatomical Optical Coherence Tomography for Long-Term, Portable, Quantitative Endoscopy

In this paper, we report on anatomical optical coherence tomography, a catheter-based optical modality designed to provide quantitative sectional images of internal hollow organ anatomy over extended observational periods. We consider the design and performance of an instrument and its initial intended application in the human upper airway for the characterization of obstructive sleep apnea (OSA). Compared with current modalities, the technique uniquely combines quantitative imaging, bedside operation, and safety for use over extended periods of time with no cumulative dose limit. Our experiments show that the instrument is capable of imaging subjects during sleep, and that it can record dynamic changes in airway size and shape.

Variability of human upper airway collapsibility during sleep and the influence of body posture and sleep stage

The critical pressure at which the pharynx collapses (Pcrit) is an objective measurement of upper airway collapsibility, an important pathogenetic factor in obstructive sleep apnoea. This study examined the inherent variability of passive Pcrit measurement during sleep and evaluated the effects of sleep stage and body posture on Pcrit. Repeated measurements of Pcrit were assessed in 23 individuals (15 male) with diagnosed obstructive sleep apnoea throughout a single overnight sleep study. Body posture and sleep stage were unrestricted. Applied upper airway pressure was repetitively reduced to obtain multiple measurements of Pcrit. In 20 subjects multiple measurements of Pcrit were obtained. The overall coefficient of repeatability for Pcrit measurement was 4.1 cm H2O. Considering only the lateral posture, the coefficient was 4.8 cm H2O. It was 3.3 cm H2O in the supine posture. Pcrit decreased from the supine to lateral posture [supine mean 2.5 cm H2O, 95% confidence interval (CI) 1.4–3.6; lateral mean 0.3 cm H2O, 95% CI −0.8–1.4, P = 0.007] but did not vary with sleep stage (P = 0.91). This study has shown that the overall coefficient of repeatability was 4.1 cm H2O, implying that the minimum detectable difference, with 95% probability, between two repeated Pcrit measurements in an individual is 4.1 cm H2O. Such variability in overnight measures of Pcrit indicates that a single unqualified value of Pcrit cannot be used to characterize an individual’s overall collapsibility during sleep. When within‐subject variability is accounted for, change in body posture from supine to lateral significantly decreases passive pharyngeal collapsibility.

Measurement, Reconstruction, and Flow-Field Computation of the Human Pharynx With Application to Sleep Apnea

Repetitive closure of the upper airway characterizes obstructive sleep apnea. It disrupts sleep causing excessive daytime drowsiness and is linked to hypertension and cardiovascular disease. Previous studies simulating the underlying fluid mechanics are based upon geometries, time-averaged over the respiratory cycle, obtained usually via MRI or CT scans. Here, we generate an anatomically correct geometry from data captured in vivo by an endoscopic optical technique. This allows quantitative real-time imaging of the internal cross section with minimal invasiveness. The steady inhalation flow field is computed using a k- shear-stress transport (SST) turbulence model. Simulations reveal flow mechanisms that produce low-pressure regions on the sidewalls of the pharynx and on the soft palate within the pharyngeal section of minimum area. Soft-palate displacement and side-wall deformations further reduce the pressures in these regions, thus creating forces that would tend to narrow the airway. These phenomena suggest a mechanism for airway closure in the lateral direction as clinically observed. Correlations between pressure and airway deformation indicate that quantitative prediction of the low-pressure regions for an individual are possible. The present predictions warrant and can guide clinical investigation to confirm the phenomenology and its quantification, while the overall approach represents an advancement toward patient-specific modeling.