David G. McSharry

Adult obstructive sleep apnoea

Obstructive sleep apnoea is an increasingly common disorder of repeated upper airway collapse during sleep, leading to oxygen desaturation and disrupted sleep. Features include snoring, witnessed apnoeas, and sleepiness. Pathogenesis varies; predisposing factors include small upper airway lumen, unstable respiratory control, low arousal threshold, small lung volume, and dysfunctional upper airway dilator muscles. Risk factors include obesity, male sex, age, menopause, fluid retention, adenotonsillar hypertrophy, and smoking. Obstructive sleep apnoea causes sleepiness, road traffic accidents, and probably systemic hypertension. It has also been linked to myocardial infarction, congestive heart failure, stroke, and diabetes mellitus though not definitively. Continuous positive airway pressure is the treatment of choice, with adherence of 60-70%. Bi-level positive airway pressure or adaptive servo-ventilation can be used for patients who are intolerant to continuous positive airway pressure. Other treatments include dental devices, surgery, and weight loss.

Adaptive Servoventilation for Treatment of Sleep-Disordered Breathing in Heart Failure: A Systematic Review and Meta-analysis

BACKGROUND Adaptive servoventilation (ASV) has demonstrated efficacy in treating sleep-disordered breathing (SDB) in patients with heart failure (HF), but large randomized trials are lacking. We, therefore, sought to perform a systematic review and meta-analysis of existing data. METHODS A systematic search of the PubMed database was undertaken in March 2012. Publications were independently assessed by two investigators to identify studies of ≥ 1-week duration that compared ASV to a control condition (ie, subtherapeutic ASV, continuous or bilevel pressure ventilation, oxygen therapy, or no treatment) in adult patients with SDB and HF. Mean, variability,and sample size data were extracted independently for the following outcomes: apneahypopnea index (AHI), left ventricular ejection fraction (LVEF), quality of life (SF-36 Health Survey; Medical Outcomes Trust), 6-min walk distance, peak oxygen consumption ( VO 2 ) % predicted, and ventilatory equivalent ratio for CO 2 ( VE / Vco 2 ) slope measured during exercise. Random effects meta-analysis models were applied. RESULTS Fourteen studies were identified (N = 538). Comparing ASV to control conditions, the weighted mean difference in AHI ( -14.64 events/h; 95% CI, -21.03 to - 8.25) and LVEF (0.40;95% CI, 0.08-0.71) both significantly favored ASV. ASV also improved the 6-min walk distance,but not peak O 2 % predicted, VE / VCO 2 slope, or quality of life, compared with control conditions. CONCLUSIONS In patients with HF and SDB, ASV was more effective than control conditions in reducing the AHI and improving cardiac function and exercise capacity. These data provide a compelling rationale for large-scale randomized controlled trials to assess the clinical impact of ASV on hard outcomes in these patients.

Clinical predictors of the respiratory arousal threshold in patients with obstructive sleep apnea.

RATIONALE A low respiratory arousal threshold (ArTH) is one of several traits involved in obstructive sleep apnea pathogenesis and may be a therapeutic target; however, there is no simple way to identify patients without invasive measurements. OBJECTIVES To determine the physiologic determinates of the ArTH and develop a clinical tool that can identify patients with low ArTH. METHODS Anthropometric data were collected in 146 participants who underwent overnight polysomnography with an epiglottic catheter to measure the ArTH (nadir epiglottic pressure before arousal). The ArTH was measured from up to 20 non-REM and REM respiratory events selected randomly. Multiple linear regression was used to determine the independent predictors of the ArTH. Logistic regression was used to develop a clinical scoring system. MEASUREMENTS AND MAIN RESULTS Nadir oxygen saturation as measured by pulse oximetry, apnea-hypopnea index, and the fraction of events that were hypopneas (Fhypopneas) were independent predictors of the ArTH (r(2) = 0.59; P < 0.001). Using this information, we used receiver operating characteristic analysis and logistic regression to develop a clinical score to predict a low ArTH, which allocated a score of 1 to each criterion that was satisfied: (apnea-hypopnea index, <30 events per hour) + (nadir oxygen saturation as measured by pulse oximetry >82.5%) + (Fhypopneas >58.3%). A score of 2 or above correctly predicted a low arousal threshold in 84.1% of participants with a sensitivity of 80.4% and a specificity of 88.0%, a finding that was confirmed using leave-one-out cross-validation analysis. CONCLUSIONS Our results demonstrate that individuals with a low ArTH can be identified from standard, clinically available variables. This finding could facilitate larger interventional studies targeting the ArTH.

Neurogenic Changes in the Upper Airway of Patients with Obstructive Sleep Apnea

RATIONALE Controversy persists regarding the presence and importance of hypoglossal nerve dysfunction in obstructive sleep apnea (OSA). OBJECTIVES We assessed quantitative parameters related to motor unit potential (MUP) morphology derived from electromyographic (EMG) signals in patients with OSA versus control subjects and hypothesized that signs of neurogenic remodeling would be present in the patients with OSA. METHODS Participants underwent diagnostic sleep studies to obtain apnea-hypopnea indices. Muscle activity was detected with 50-mm concentric needle electrodes. The concentric needle was positioned at more than 10 independent sites per subject, after the local anatomy of the upper airway musculature was examined by ultrasonography. All activity was quantified with subjects awake, during supine eupneic breathing while wearing a nasal mask connected to a pneumotachograph. Genioglossus EMG signals were analyzed offline by automated software (DQEMG), which extracted motor unit potential trains (MUPTs) contributed by individual motor units from the composite EMG signals. Quantitative measurements of MUP templates, including duration, peak-to-peak amplitude, area, area-to-amplitude ratio, and size index, were compared between the untreated patients with OSA and healthy control subjects. MEASUREMENTS AND MAIN RESULTS A total of 1,655 MUPTs from patients with OSA (n = 17; AHI, 55 ± 6/h) and control subjects (n = 14; AHI, 4 ± 1/h) were extracted from the genioglossus muscle EMG signals. MUP peak-to-peak amplitudes in the patients with OSA were not different compared with the control subjects (397.5 ± 9.0 vs. 382.5 ± 10.0 μV). However, the MUPs of the patients with OSA were longer in duration (11.5 ± 0.1 vs. 10.3 ± 0.1 ms; P < 0.001) and had a larger size index (4.09 ± 0.02 vs. 3.92 ± 0.02; P < 0.001) compared with control subjects. CONCLUSIONS These results confirm and quantify the extent and existence of structural neural remodeling in OSA.

Sleep quality in chronic obstructive pulmonary disease

Background and objective:  Previous reports have shown that patients with chronic obstructive pulmonary disease (COPD) sleep poorly, but the underlying basis remains speculative. The aim of this retrospective study was to determine potential predictors of poor sleep quality in COPD patients.

Trazodone Effects on Obstructive Sleep Apnea and Non-REM Arousal Threshold

RATIONALE A low respiratory arousal threshold is a physiological trait involved in obstructive sleep apnea (OSA) pathogenesis. Trazodone may increase arousal threshold without compromising upper airway muscles, which should improve OSA. OBJECTIVES We aimed to examine how trazodone alters OSA severity and arousal threshold. We hypothesized that trazodone would increase the arousal threshold and improve the apnea/hypopnea index (AHI) in selected patients with OSA. METHODS Subjects were studied on two separate nights in a randomized crossover design. Fifteen unselected subjects with OSA (AHI ≥ 10/h) underwent a standard polysomnogram plus an epiglottic catheter to measure the arousal threshold. Subjects were studied after receiving trazodone (100 mg) and placebo, with 1 week between conditions. The arousal threshold was calculated as the nadir pressure before electrocortical arousal from approximately 20 spontaneous respiratory events selected randomly. MEASUREMENTS AND MAIN RESULTS Compared with placebo, trazodone resulted in a significant reduction in AHI (38.7 vs. 28.5 events/h, P = 0.041), without worsening oxygen saturation or respiratory event duration. Trazodone was not associated with a significant change in the non-REM arousal threshold (-20.3 vs. -19.3 cm H2O, P = 0.51) compared with placebo. In subgroup analysis, responders to trazodone spent less time in N1 sleep (20.1% placebo vs. 9.0% trazodone, P = 0.052) and had an accompanying reduction in arousal index, whereas nonresponders were not observed to have a change in sleep parameters. CONCLUSIONS These findings suggest that trazodone could be effective therapy for patients with OSA without worsening hypoxemia. Future studies should focus on underlying mechanisms and combination therapies to eliminate OSA. Clinical trial registered with www.clinicaltrials.gov (NCT 01817907).

A mechanism for upper airway stability during slow wave sleep.

STUDY OBJECTIVES The severity of obstructive sleep apnea is diminished (sometimes markedly) during slow wave sleep (SWS). We sought to understand why SWS stabilizes the upper airway. Increased single motor unit (SMU) activity of the major upper airway dilating muscle (genioglossus) should improve upper airway stability. Therefore, we hypothesized that genioglossus SMUs would increase their activity during SWS in comparison with Stage N2 sleep. DESIGN The activity of genioglossus SMUs was studied on both sides of the transition between Stage N2 sleep and SWS. SETTING Sleep laboratory. PARTICIPANTS Twenty-nine subjects (age 38 ± 13 yr, 17 males) were studied. INTERVENTION SWS. MEASUREMENT AND RESULTS Subjects slept overnight with fine-wire electrodes in their genioglossus muscles and with full polysomnographic and end tidal carbon dioxide monitors. Fifteen inspiratory phasic (IP) and 11 inspiratory tonic (IT) units were identified from seven subjects and these units exhibited significantly increased inspiratory discharge frequencies during SWS compared with Stage N2 sleep. The peak discharge frequency of the inspiratory units (IP and IT) was 22.7 ± 4.1 Hz in SWS versus 20.3 ± 4.5 Hz in Stage N2 (P < 0.001). The IP units also fired for a longer duration (expressed as a percentage of inspiratory time) during SWS (104.6 ± 39.5 %TI) versus Stage N2 sleep (82.6 ± 39.5 %TI, P < 0.001). The IT units fired faster during expiration in SWS (14.2 ± 1.8 Hz) versus Stage N2 sleep (12.6 ± 3.1 Hz, P = 0.035). There was minimal recruitment or derecruitment of units between SWS and Stage N2 sleep. CONCLUSION Increased genioglossus SMU activity likely makes the airway more stable and resistant to collapse throughout the respiratory cycle during SWS.

Evaluation of Right Ventricular Remodeling Using Cardiac Magnetic Resonance Imaging in Co-Existent Chronic Obstructive Pulmonary Disease and Obstructive Sleep Apnea

Abstract Untreated chronic obstructive pulmonary disease (COPD) co-existing with obstructive sleep apnea (OSA), also known as overlap syndrome, has higher cardiovascular mortality than COPD alone but its underlying mechanism remains unclear. We hypothesize that the presence of overlap syndrome is associated with more extensive right ventricular (RV) remodeling compared to patients with COPD alone. Adult COPD patients (GOLD stage 2 or higher) with at least 10 pack-years of smoking history were included. Overnight laboratory-based polysomnography was performed to test for OSA. Subjects with an apnea-hypopnea index (AHI) >10/h were classified as having overlap syndrome (n = 7), else classified as having COPD-only (n = 11). A cardiac MRI was performed to assess right and left cardiac chambers sizes, ventricular masses, and cine function. RV mass index (RVMI) was markedly higher in the overlap group than the COPD-only group (19 ± 6 versus 11 ± 6; p = 0.02). Overlap syndrome subjects had a reduced RV remodeling index (defined as the ratio between RVMI and RV end-diastolic volume index) compared to the COPD-only group (0.27 ± 0.06 versus 0.18 ± 0.08; p = 0.02). In the overlap syndrome subjects, the extent of RV remodeling was associated with severity of oxygen desaturation (R2 = 0.65, p = 0.03). Our pilot results suggest that untreated overlap syndrome may cause more extensive RV remodeling than COPD alone.

Physiological mechanisms of upper airway hypotonia during REM sleep.

STUDY OBJECTIVES Rapid eye movement (REM)-induced hypotonia of the major upper airway dilating muscle (genioglossus) potentially contributes to the worsening of obstructive sleep apnea that occurs during this stage. No prior human single motor unit (SMU) study of genioglossus has examined this possibility to our knowledge. We hypothesized that genioglossus SMUs would reduce their activity during stable breathing in both tonic and phasic REM compared to stage N2 sleep. Further, we hypothesized that hypopneas occurring in REM would be associated with coincident reductions in genioglossus SMU activity. DESIGN The activity of genioglossus SMUs was studied in (1) neighboring epochs of stage N2, and tonic and phasic REM; and (2) during hypopneas occurring in REM. SETTING Sleep laboratory. PARTICIPANTS 29 subjects (38 ± 13 y) (17 male). INTERVENTION Natural sleep, including REM sleep and REM hypopneas. MEASUREMENT AND RESULTS Subjects slept overnight with genioglossus fine-wire intramuscular electrodes and full polysomnography. Forty-two SMUs firing during one or more of stage N2, tonic REM, or phasic REM were sorted. Twenty inspiratory phasic (IP), 17 inspiratory tonic (IT), and five expiratory tonic (ET) SMUs were characterized. Fewer units were active during phasic REM (23) compared to tonic REM (30) and stage N2 (33). During phasic REM sleep, genioglossus IP and IT SMUs discharged at slower rates and for shorter durations than during stage N2. For example, the SMU peak frequency during phasic REM 5.7 ± 6.6 Hz (mean ± standard deviation) was less than both tonic REM 12.3 ± 9.7 Hz and stage N2 16.1 ± 10.0 Hz (P < 0.001). The peak firing frequencies of IP/IT SMUs decreased from the last breath before to the first breath of a REM hypopnea (11.8 ± 10.9 Hz versus 5.7 ± 9.4 Hz; P = 0.001). CONCLUSION Genioglossus single motor unit activity is significantly reduced in REM sleep, particularly phasic REM. Single motor unit activity decreases abruptly at the onset of REM hypopneas.

Genioglossus fatigue in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a prevalent disorder that may cause cardiovascular disease and fatal traffic accidents but the pathophysiology remains incompletely understood. Increased fatigability of the genioglossus (the principal upper airway dilator muscle) might be important in OSA pathophysiology but the existing literature is uncertain. We hypothesized that the genioglossus in OSA subjects would fatigue more than in controls. In 9 OSA subjects and 9 controls during wakefulness we measured maximum voluntary tongue protrusion force (Tpmax). Using surface electromyography arrays we measured the rate of decline in muscle fiber conduction velocity (MFCV) during an isometric fatiguing contraction at 30% Tpmax. The rate of decline in MFCV provides an objective means of quantifying localized muscle fatigue. Linear regression analysis of individual subject data demonstrated a significantly greater decrease in MFCV in OSA subjects compared to control subjects (29.2 ± 20.8% [mean ± SD] versus 11.2 ± 20.8%; p=0.04). These data support increased fatigability of the genioglossus muscle in OSA subjects which may be important in the pathophysiology of OSA.