Peter G. Catcheside

Nocturnal non-invasive nasal ventilation in stable hypercapnic COPD: a randomised controlled trial

Background: Sleep hypoventilation has been proposed as a cause of progressive hypercapnic respiratory failure and death in patients with severe chronic obstructive pulmonary disease (COPD). A study was undertaken to determine the effects of nocturnal non-invasive bi-level pressure support ventilation (NIV) on survival, lung function and quality of life in patients with severe hypercapnic COPD. Method: A multicentre, open-label, randomised controlled trial of NIV plus long-term oxygen therapy (LTOT) versus LTOT alone was performed in four Australian University Hospital sleep/respiratory medicine departments in patients with severe stable smoking-related COPD (forced expiratory volume in 1 s (FEV1.0) <1.5 litres or <50% predicted and ratio of FEV1.0 to forced vital capacity (FVC) <60% with awake arterial carbon dioxide tension (Paco2) >46 mm Hg and on LTOT for at least 3 months) and age <80 years. Patients with sleep apnoea (apnoea-hypopnoea index >20/h) or morbid obesity (body mass index >40) were excluded. Outcome measures were survival, spirometry, arterial blood gases, polysomnography, general and disease-specific quality of life and mood. Results: 144 patients were randomised (72 to NIV + LTOT and 72 to LTOT alone). NIV improved sleep quality and sleep-related hypercapnia acutely, and patients complied well with therapy (mean (SD) nightly use 4.5 (3.2) h). Compared with LTOT alone, NIV (mean follow-up 2.21 years, range 0.01–5.59) showed an improvement in survival with the adjusted but not the unadjusted Cox model (adjusted hazard ratio (HR) 0.63, 95% CI 0.40 to 0.99, p = 0.045; unadjusted HR 0.82, 95% CI 0.53 to 1.25, p = NS). FEV1.0 and Paco2 measured at 6 and 12 months were not different between groups. Patients assigned to NIV + LTOT had reduced general and mental health and vigour. Conclusions: Nocturnal NIV in stable oxygen-dependent patients with hypercapnic COPD may improve survival, but this appears to be at the cost of worsening quality of life. Trial registration number: ACTRN12605000205639

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.

Primary care vs specialist sleep center management of obstructive sleep apnea and daytime sleepiness and quality of lIfe: a randomized trial

IMPORTANCE Due to increasing demand for sleep services, there has been growing interest in ambulatory models of care for patients with obstructive sleep apnea. With appropriate training and simplified management tools, primary care physicians are ideally positioned to take on a greater role in diagnosis and treatment. OBJECTIVE To compare the clinical efficacy and within-trial costs of a simplified model of diagnosis and care in primary care relative to that in specialist sleep centers. DESIGN, SETTING, AND PATIENTS A randomized, controlled, noninferiority study involving 155 patients with obstructive sleep apnea that was treated at primary care practices (n=81) in metropolitan Adelaide, 3 rural regions of South Australia or at a university hospital sleep medicine center in Adelaide, Australia (n = 74), between September 2008 and June 2010. INTERVENTIONS Primary care management of obstructive sleep apnea vs usual care in a specialist sleep center; both plans included continuous positive airway pressure, mandibular advancement splints, or conservative measures only. MAIN OUTCOME AND MEASURES The primary outcome was 6-month change in Epworth Sleepiness Scale (ESS) score, which ranges from 0 (no daytime sleepiness) to 24 points (high level of daytime sleepiness). The noninferiority margin was -2.0. Secondary outcomes included disease-specific and general quality of life measures, obstructive sleep apnea symptoms, adherence to using continuous positive airway pressure, patient satisfaction, and health care costs. RESULTS There were significant improvements in ESS scores from baseline to 6 months in both groups. In the primary care group, the mean baseline score of 12.8 decreased to 7.0 at 6 months (P < .001), and in the specialist group, the score decreased from a mean of 12.5 to 7.0 (P < .001). Primary care management was noninferior to specialist management with a mean change in ESS score of 5.8 vs 5.4 (adjusted difference, -0.13; lower bound of 1-sided 95% CI, -1.5; P = .43). There were no differences in secondary outcome measures between groups. Seventeen patients (21%) withdrew from the study in the primary care group vs 6 patients (8%) in the specialist group. CONCLUSIONS AND RELEVANCE Among patients with obstructive sleep apnea, treatment under a primary care model compared with a specialist model did not result in worse sleepiness scores, suggesting that the 2 treatment modes may be comparable. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12608000514303.

A simplified model of screening questionnaire and home monitoring for obstructive sleep apnoea in primary care

Background To address the growing burden of disease and long waiting lists for sleep services, a simplified two-stage model was developed and validated for identifying obstructive sleep apnoea (OSA) in primary care using a screening questionnaire followed by home sleep monitoring. Methods 157 patients aged 25–70 years attending their primary care physician for any reason at six primary care clinics in rural and metropolitan regions of South Australia participated. The first 79 patients formed the development group and the next 78 patients the validation group. A screening questionnaire was developed from factors identified from sleep surveys, demographic and anthropometric data to be predictive of moderate to severe OSA. Receiver operating characteristic (ROC) curve analysis was used to validate the two-channel ApneaLink device against full polysomnography. The diagnostic accuracy of the overall two-stage model was then evaluated. Results Snoring, waist circumference, witnessed apnoeas and age were predictive of OSA and incorporated into a screening questionnaire (ROC area under curve (AUC) 0.84, 95% CI 0.75 to 0.94, p<0.001). ApneaLink oximetry with a 3% dip rate was highly predictive of OSA (AUC 0.96, 95% CI 0.91 to 1.0, p<0.001). The two-stage diagnostic model showed a sensitivity of 0.97 (95% CI 0.81 to 1.00) and specificity of 0.87 (95% CI 0.74 to 0.95) in the development group, and a sensitivity of 0.88 (95% CI 0.60 to 0.98) and specificity of 0.82 (95% CI 0.70 to 0.90) in the validation group. Conclusion A two-stage model of screening questionnaire followed by home oximetry can accurately identify patients with OSA in primary care and has the potential to expedite care for patients with this common sleep disorder.

Sleep hypoventilation in hypercapnic chronic obstructive pulmonary disease: prevalence and associated factors

Sleep hypoventilation (SH) may be important in the development of hypercapnic respiratory failure in chronic obstructive pulmonary disease (COPD). The prevalence of SH, associated factors, and overnight changes in waking arterial blood gases (ABG), were assessed in 54 stable hypercapnic COPD patients without concomitant sleep apnoea or morbid obesity. Lung function assessment, anthropomorphic measurements, and polysomnography with ABG measurement before and after sleep were conducted in all patients. Transcutaneous carbon dioxide tension (Pt,CO2) was measured in sleep, using simultaneous arterial carbon dioxide tension (Pa,CO2) for in vivo calibration and to correct for drift in the sensor. Of the patients, 43% spent ≥20% of sleep time with Pt,CO2 >1.33 kPa (10 mmHg) above waking baseline. Severity of SH was best predicted by a combination of baseline Pa,CO2, body mass index and per cent rapid-eye movement (REM) sleep. REM-related hypoventilation correlated significantly with severity of inspiratory flow limitation in REM, and with apnoea/hypopnoea index. Pa,CO2 increased mean±sd 0.70±0.65 kPa (5.29±4.92 mmHg) from night to morning, and this change was highly significant. The change in Pa,CO2 was strongly correlated with severity of SH. Sleep hypoventilation is common in hypercapnic chronic obstructive pulmonary disease, and related to baseline arterial carbon dioxide tension, body mass index and indices of upper airway obstruction. Sleep hypoventilation is associated with significant increases in arterial carbon dioxide tension night-to-morning, and may contribute to long-term elevations in arterial carbon dioxide tension.

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.

Accurate Position Monitoring and Improved Supine-Dependent Obstructive Sleep Apnea with a New Position Recording and Supine Avoidance Device

STUDY OBJECTIVES Approximately 30% of obstructive sleep apnea (OSA) patients have supine-predominant OSA, and simply avoiding supine sleep should normalise respiratory disturbance event rates. However, traditional supine-avoidance therapies are inherently uncomfortable, and treatment adherence is poor and difficult to monitor objectively. This study evaluated the efficacy of a novel, potentially more acceptable position monitor and supine-avoidance device for managing supine-predominant OSA and snoring. DESIGN AND SETTING In-laboratory evaluation of position recording accuracy versus video recordings (validation study), and randomized controlled crossover trial of active versus inactive supine-avoidance therapy in the home setting (efficacy study). PATIENTS 17 patients undergoing in-laboratory sleep studies (validation) and 15 patients with supine-predominant OSA (efficacy). INTERVENTIONS EFFICACY STUDY: 1 week of inactive and 1 week of active treatment in randomized order, separated by 1 week. MEASUREMENTS AND RESULTS Agreement between 30-sec epoch-based posture classifications from device versus video records was high (median κ 0.95, interquartile range: 0.88-1.00), and there was good supine time agreement (bias 0.3%, 95%CI: -4.0% to 4.6%). In the efficacy study, apnea-hypopnea index (AHI) and snoring frequency were measured in-home using a nasal pressure and microphone based system during inactive and active treatment weeks. The position monitoring and supine alarm device markedly inhibited supine time (mean ± SEM 19.3% ± 4.3% to 0.4% ± 0.3%, p < 0.001) and reduced AHI (25.0 ± 1.7 to 13.7 ± 1.1 events/h, p = 0.030) but not snoring frequency. CONCLUSIONS This new position monitoring and supine alarm device records sleep position accurately and improves OSA but not snoring in patients with supine-predominant OSA.

Effect of CPAP on intrinsic PEEP, inspiratory effort, and lung volume in severe stable COPD

Background: Intrinsic positive end expiratory pressure (PEEPi) constitutes an inspiratory threshold load on the respiratory muscles, increasing work of breathing. The role of continuous positive airway pressure (CPAP) in alleviating PEEPi in patients with severe stable chronic obstructive pulmonary disease is uncertain. This study examined the effect of CPAP on the inspiratory threshold load, muscle effort, and lung volume in this patient group. Methods: Nine patients were studied at baseline and with CPAP increasing in increments of 1 cm H2O to a maximum of 10 cm H2O. Breathing pattern and minute ventilation (V̇i), dynamic PEEPi, expiratory muscle activity, diaphragmatic (PTPdi/min) and oesophageal (PTPoes/min) pressure-time product per minute, integrated diaphragmatic (EMGdi) and intercostal EMG (EMGic) and end expiratory lung volume (EELV) were measured. Results: Expiratory muscle activity was present at baseline in one subject. In the remaining eight, PEEPi was reduced from a mean (SE) of 2.9 (0.6) cm H2O to 0.9 (0.1) cm H2O (p<0.05). In two subjects expiratory muscle activity contributed to PEEPi at higher pressures. There were no changes in respiratory pattern but V̇i increased from 9.2 (0.6) l/min to 10.7 (1.1) l/min (p<0.05). EMGdi remained stable while EMGic increased significantly. PTPoes/min decreased, although this did not reach statistical significance. PTPdi/min decreased significantly from 242.1 (32.1) cm H2O.s/min to 112.9 (21.7) cm H2O.s/min). EELV increased by 1.1 (0.3) l (p<0.01). Conclusion: High levels of CPAP reduce PEEPi and indices of muscle effort in patients with severe stable COPD, but only at the expense of substantial increases in lung volume.

Genioglossus reflex inhibition to upper-airway negative-pressure stimuli during wakefulness and sleep in healthy males

During wakefulness, obstructive sleep apnoea patients appear to compensate for an anatomically narrow upper airway by increasing upper airway dilator muscle activity, e.g. genioglossus, at least partly via a negative‐pressure reflex that may be diminished in sleep. Previous studies have assessed the negative‐pressure reflex using multi‐unit, rectified, moving‐time‐average EMG recordings during brief pulses of negative upper‐airway pressure. However, moving‐time averaging probably obscures the true time‐related reflex morphology, potentially masking transient excitatory and inhibitory components. This study aimed to re‐examine the genioglossus negative‐pressure reflex in detail, without moving‐time averaging. Bipolar fine‐wire electrodes were inserted per orally into the genioglossus muscle in 17 healthy subjects. Two upper airway pressure catheters were inserted per nasally. Genioglossus EMG reflex responses were generated via negative‐pressure stimuli (∼−10 cmH2O at the choanae, 250 ms duration) delivered during wakefulness and sleep. Ensemble‐averaged, rectified, genioglossus EMG recordings demonstrated reflex activation (onset latency 26 ± 1 ms; peak amplitude 231 ± 29% of baseline) followed by a previously unreported suppression (peak latency 71 ± 4 ms; 67 ± 8% of baseline). Single‐motor‐unit activity, clearly identifiable in ∼10% of trials in six subjects, showed a concomitant increase in the interspike interval from baseline (26 ± 9 ms, P= 0.01). Genioglossus negative‐pressure reflex morphology and amplitude of the initial peak were maintained in non‐rapid eye movement (NREM) sleep but suppression amplitude was more pronounced during NREM and declined further during REM sleep compared to wakefulness. These data indicate there are both excitatory and inhibitory components to the genioglossus negative‐pressure reflex which are differentially affected by state.

The influence of gender and upper airway resistance on the ventilatory response to arousal in obstructive sleep apnoea in humans

The termination of obstructive respiratory events is typically associated with arousal from sleep. The ventilatory response to arousal may be an important determinant of subsequent respiratory stability/instability and therefore may be involved in perpetuating obstructive respiratory events. In healthy subjects arousal is associated with brief hyperventilation followed by more prolonged hypoventilation on return to sleep. This study was designed to assess whether elevated sleeping upper airway resistance (RUA) alters the ventilatory response to arousal and subsequent breathing on return to sleep in patients with obstructive sleep apnoea (OSA). Inspired minute ventilation (VI), RUA and end‐tidal CO2 pressure (PET,CO2) were measured in 22 patients (11 men, 11 women) with OSA (mean ±s.e.m., apnoea–hypopnoea index (AHI) 48.9 ± 5.9 events h−1) during non‐rapid eye movement (NREM) sleep with low RUA (2.8 ± 0.3 cmH2O l−1 s; optimal continuous positive airway pressure (CPAP) = 11.3 ± 0.7 cmH2O) and with elevated RUA (17.6 ± 2.8 cmH2O l−1 s; sub‐optimal CPAP = 8.4 ± 0.8 cmH2O). A single observer, unaware of respiratory data, identified spontaneous and tone‐induced arousals of 3–15 s duration preceded and followed by stable NREM sleep. VI was compared between CPAP levels before and after spontaneous arousal in 16 subjects with tone‐induced arousals in both conditions. During stable NREM sleep at sub‐optimal CPAP, PET,CO2 was mildly elevated (43.5 ± 0.8 versus 42.5 ± 0.8 Torr). However, baseline VI (7.8 ± 0.3 versus 8.0 ± 0.3 l min−1) was unchanged between CPAP conditions. For the first three breaths following arousal, VI was higher for sub‐optimal than optimal CPAP (first breath: 11.2 ± 0.9 versus 9.3 ± 0.6 l min−1). The magnitude of hypoventilation on return to sleep was not affected by the level of CPAP and both obstructive and central respiratory events were rare following arousal. Similar results occurred after tone‐induced arousals which led to larger responses than spontaneous arousals. VI for the first breath following arousal under optimal CPAP was greater in men than women (11.0 ± 0.4 versus 7.6 ± 0.6 l min−1). These results demonstrate that the ventilatory response to arousal is influenced by pre‐arousal airway resistance and gender. Whether this contributes to the perpetuation of respiratory events and the pathogenesis of OSA is unclear.