Yuanming Luo

CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea

BACKGROUND Obstructive sleep apnea is associated with an increased risk of cardiovascular events; whether treatment with continuous positive airway pressure (CPAP) prevents major cardiovascular events is uncertain. METHODS After a 1-week run-in period during which the participants used sham CPAP, we randomly assigned 2717 eligible adults between 45 and 75 years of age who had moderate-to-severe obstructive sleep apnea and coronary or cerebrovascular disease to receive CPAP treatment plus usual care (CPAP group) or usual care alone (usual-care group). The primary composite end point was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack. Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood. RESULTS Most of the participants were men who had moderate-to-severe obstructive sleep apnea and minimal sleepiness. In the CPAP group, the mean duration of adherence to CPAP therapy was 3.3 hours per night, and the mean apnea-hypopnea index (the number of apnea or hypopnea events per hour of recording) decreased from 29.0 events per hour at baseline to 3.7 events per hour during follow-up. After a mean follow-up of 3.7 years, a primary end-point event had occurred in 229 participants in the CPAP group (17.0%) and in 207 participants in the usual-care group (15.4%) (hazard ratio with CPAP, 1.10; 95% confidence interval, 0.91 to 1.32; P=0.34). No significant effect on any individual or other composite cardiovascular end point was observed. CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood. CONCLUSIONS Therapy with CPAP plus usual care, as compared with usual care alone, did not prevent cardiovascular events in patients with moderate-to-severe obstructive sleep apnea and established cardiovascular disease. (Funded by the National Health and Medical Research Council of Australia and others; SAVE ClinicalTrials.gov number, NCT00738179 ; Australian New Zealand Clinical Trials Registry number, ACTRN12608000409370 .).

The value of multiple tests of respiratory muscle strength

Background: Respiratory muscle weakness is an important clinical problem. Tests of varying complexity and invasiveness are available to assess respiratory muscle strength. The relative precision of different tests in the detection of weakness is less clear, as is the value of multiple tests. Methods: The respiratory muscle function tests of clinical referrals who had multiple tests assessed in our laboratories over a 6-year period were analysed. Thresholds for weakness for each test were determined from published and in-house laboratory data. The patients were divided into three groups: those who had all relevant measurements of global inspiratory muscle strength (group A, n = 182), those with full assessment of diaphragm strength (group B, n = 264) and those for whom expiratory muscle strength was fully evaluated (group C, n = 60). The diagnostic outcome of each inspiratory, diaphragm and expiratory muscle test, both singly and in combination, was studied and the impact of using more than one test to detect weakness was calculated. Results: The clinical referrals were primarily for the evaluation of neuromuscular diseases and dyspnoea of unknown cause. A low maximal inspiratory mouth pressure (Pimax) was recorded in 40.1% of referrals in group A, while a low sniff nasal pressure (Sniff Pnasal) was recorded in 41.8% and a low sniff oesophageal pressure (Sniff Poes) in 37.9%. When assessing inspiratory strength with the combination of all three tests, 29.6% of patients had weakness. Using the two non-invasive tests (Pimax and Sniff Pnasal) in combination, a similar result was obtained (low in 32.4%). Combining Sniff Pdi (low in 68.2%) and Twitch Pdi (low in 67.4%) reduced the diagnoses of patients with diaphragm weakness to 55.3% in group B. 38.3% of the patients in group C had expiratory muscle weakness as measured by maximum expiratory pressure (Pemax) compared with 36.7% when weakness was diagnosed by cough gastric pressure (Pgas), and 28.3% when assessed by Twitch T10. Combining all three expiratory muscle tests reduced the number of patients diagnosed as having expiratory muscle weakness to 16.7%. Conclusion: The use of single tests such as Pimax, Pemax and other available individual tests of inspiratory, diaphragm and expiratory muscle strength tends to overdiagnose weakness. Combinations of tests increase diagnostic precision and, in the population studied, they reduced the diagnosis of inspiratory, specific diaphragm and expiratory muscle weakness by 19–56%. Measuring both Pimax and Sniff Pnasal resulted in a relative reduction of 19.2% of patients falsely diagnosed with inspiratory muscle weakness. The addition of Twitch Pdi to Sniff Pdi increased diagnostic precision by a smaller amount (18.9%). Having multiple tests of respiratory muscle function available both increases diagnostic precision and makes assessment possible in a range of clinical circumstances.

Predictors of long-term adherence to continuous positive airway pressure therapy in patients with obstructive sleep apnea and cardiovascular disease in the SAVE study

STUDY OBJECTIVES To determine the clinical variables that best predict long- term continuous positive airway pressure (CPAP) adherence among patients with cardiovascular disease who have obstructive sleep apnea (OSA). DESIGN 12-mo prospective within-trial observational study. SETTING Centers in China, Australia, and New Zealand participating in the Sleep Apnea cardioVascular Endpoints (SAVE) study. PATIENTS There were 275 patients age 45-70 y with cardiovascular disease (i.e., previously documented transient ischemic attack, stroke, or coronary artery disease) and OSA (4% oxygen desaturation index (ODI) > 12) who were randomized into the CPAP arm of the SAVE trial prior to July 1, 2010. METHODS Age, sex, country of residence, type of cardiovascular disease, baseline ODI, severity of sleepiness, and Hospital Anxiety and Depression Scale (HADS) scores plus CPAP side effects and adherence at 1 mo were entered in univariate analyses in an attempt to identify factors predictive of CPAP adherence at 12 mo. Variables with P < 0.2 were then included in a multivariate analysis using a linear mixed model with sites as a random effect and 12-mo CPAP use as the dependent outcome variable. MEASUREMENTS AND RESULTS CPAP adherence at 1, 6, and 12 mo was (mean ± standard deviation) 4.4 ± 2.0, 3.8 ± 2.3, and 3.3 ± 2.4 h/night, respectively. CPAP use at 1 mo (effect estimate ± standard error, 0.65 ± 0.07 per h increase, P < 0.001) and side effects at 1 mo (-0.24 ± 0.092 per additional side effect, P = 0.009) were the only independent predictors of 12- mo CPAP adherence. CONCLUSION Continuous positive airway pressure use in patients with coexisting cardiovascular disease and moderate to severe obstructive sleep apnea decreases significantly over 12 months. This decline can be predicted by early patient experiences with continuous positive airway pressure (i.e., adherence and side effects at 1 month), raising the possibility that intensive early interventions could improve long-term continuous positive airway pressure compliance in this patient population. CLINICAL TRIALS REGISTER Clinical Trials, http://www.clinicaltrials.gov, NCT00738179.

Distinguishing Obstructive From Central Sleep Apnea Events: Diaphragm Electromyogram and Esophageal Pressure Compared

BACKGROUND Distinguishing central sleep apnea (CSA) from obstructive sleep apnea (OSA) can be clinically important because different types of apnea may require different treatment approaches. Academically, this distinction is important for investigating the pathological mechanism of different types of sleep apnea. Conventional polysomnography (PSG) with recording of chest and abdominal movement may overestimate the frequency of CSA, leading to inappropriate treatment of sleep-disordered breathing. We hypothesized that diaphragm electromyogram (EMGdi) could be a useful technique to assess neural respiratory drive and respiratory effort and, therefore, to distinguish accurately CSA from OSA. METHODS A multipair esophageal electrode catheter mounted with a balloon was used to record the EMGdi and esophageal pressure (Pes) during overnight PSG. Nineteen patients were included in the study, 12 of whom had previously been identified as having central apnea-hypopnea on a diagnostic PSG undertaken for symptoms that suggest OSA and 7 of whom were known to have heart failure. RESULTS A good relationship was found between the swing of Pes and the root mean (+/- SD) square of the EMGdi during OSA events (0.89 +/- 0.10). About one third of CSA events diagnosed by uncalibrated respiratory inductance plethysmography could not be confirmed by Pes or EMGdi. No difference was found in the number of CSAs diagnosed by Pes (1,319) vs EMGdi (1,293; p > 0.01). CONCLUSIONS We conclude that both Pes and EMGdi measurements are useful in accurately differentiating central from obstructive respiratory events. Conventional PSG with recording of chest and abdominal movement overestimates the frequency of CSA events.

Continuous Transcutaneous Submental Electrical Stimulation in Obstructive Sleep Apnea: A Feasibility Study

BACKGROUND The therapeutic value of transcutaneous electrical stimulation of the genioglossus muscle in patients with obstructive sleep apnea (OSA) to reduce sleep-disordered breathing is unclear. METHODS Contraction of the genioglossus muscles during transcutaneous stimulation was investigated using ultrasonography in 11 healthy subjects (seven men, mean [SD] age 30 [6] years; BMI, 24.2 [3.5] kg/m(2)). Esophageal and gastric pressures were measured with balloon catheters, and transesophageal diaphragm electromyogram (EMGdi) was recorded during polysomnography in 11 patients with OSA (eight men, aged 51 [16] years; BMI, 42.0 [9.7] kg/m(2)) while transcutaneous electrical stimulation of the genioglossus was applied in non-rapid eye movement sleep (stage N2). RESULTS Ultrasonography measurements showed a significant increase in tongue diameter during stimulation (sagittal: 10.0% [2.8%]; coronal: 9.4 % [3.7%]). The measurements were reproducible and repeatable. In patients with OSA, snoring decreased during stimulation (P < .001) and oxygenation improved (P = .001); the respiratory disturbance index (RDI) fell from 28.1 (26.3) to 10.2 (10.2) events per hour during stimulation (P = .002), returning to 26.6 (26.0) events per hour after stimulation was stopped. Transdiaphragmatic pressure swing decreased from 24.1 (13.5) cm H(2)O to 19.7 (7.1) cm H(2)O (P = .022), increasing to 24.2 (10.8) cm H(2)O afterward, and EMGdi fell from 23.8% max (12.6% max) to 15.7% max (6.4% max) (P < .001), rising to 22.6% max (10.4% max) post stimulation. CONCLUSIONS Continuous transcutaneous electrical stimulation of the genioglossus contracts the genioglossus muscle and reduces ventilatory load and neural respiratory drive in patients with OSA.

Neural respiratory drive during apnoeic events in obstructive sleep apnoea

For a given neural drive, oesophageal pressure during apnoeic episodes may differ from that during airflow, since inspiratory airflow and increased lung volume both reduce pressure generation. It was, therefore, hypothesised that diaphragm electromyography (EMG) may provide additional data to oesophageal pressure when used for the assessment of neural drive in patients with obstructive sleep apnoea, whose breathing is associated with variable airflow and changes in lung volume. Neural respiratory drive was assessed using diaphragm EMG recorded from multipair oesophageal electrodes in 12 patients with obstructive sleep apnoea. Oesophageal pressure was also recorded. The mean±sd inspiratory oesophageal pressure swing was 11.0±3.7 cmH2O during wakefulness, 38.2±15.7 cmH2O at the end of the apnoea and reduced to 28.5±10.4 cmH2O at the beginning of arousal. The mean peak inspiratory diaphragm EMG signal was 21.8±6.5 μV during wakefulness, 38.6±14.0 μV at the end of the apnoea and further increased to 59.6±32.0 μV at the beginning of arousal. It was concluded that the pattern of neural drive assessed by oesophageal pressure differs from that measured by diaphragm electromyography during apnoeic events and, therefore, that diaphragm electromyography may be a useful adjunct to measurement of oesophageal pressure for the assessment of neural drive in patients with obstructive sleep apnoea.

Efficiency of Neural Drive During Exercise in Patients With COPD and Healthy Subjects

BACKGROUND It is unknown whether efficiency of neural drive as expressed by a ratio of ventilation to the diaphragm electromyogram (EMGdi) in patients with COPD differs from that of healthy subjects during exercise and whether maximal neural drive is exhibited at the point of exercise termination. METHODS We studied 12 male patients with COPD (mean ± SD age, 62.8 ± 10.3 years; FEV(1), 28.1 ± 10.2% predicted) and 12 age- and sex-matched healthy subjects (age, 61.1 ± 7.2 years, FEV(1), 101.5 ± 11.9% predicted). EMGdi was recorded from a multipair esophageal electrode during a constant work (80% of maximal oxygen consumption derived from a previous incremental exercise test) treadmill exercise. Minute ventilation and oxygen consumption were also measured. RESULTS Root mean square (RMS) of the EMGdi increased initially and reached a plateau at submaximal drive during constant load exercise in both patients with COPD and healthy subjects. The ratio of ventilation to EMGdi remained stable during exercise in healthy subjects from beginning to the end (100% ± 70% at the beginning and 100% ± 39% at the end, P > .05), whereas the ratio decreased gradually during exercise in patients with COPD (from 85% ± 66% to 42% ± 13%, P < .05). CONCLUSIONS Efficiency of neural drive decreases in patients with COPD during treadmill exercise. Neural respiratory drive reached a submaximal plateau during constant load exercise in both healthy subjects and patients with COPD, indicating that it may not be the only factor determining exercise capacity.

Effect of brachial plexus co-activation on phrenic nerve conduction time

BACKGROUND Diaphragm function can be assessed by electromyography of the diaphragm during electrical phrenic nerve stimulation (ES). Whether phrenic nerve conduction time (PNCT) and diaphragm electrical activity can be reliably measured from chest wall electrodes with ES is uncertain. METHODS The diaphragm compound muscle action potential (CMAP) was recorded using an oesophageal electrode and lower chest wall electrodes during ES in six normal subjects. Two patients with bilateral diaphragm paralysis were also studied. Stimulations were deliberately given in a manner designed to avoid or incur co-activation of the brachial plexus. RESULTS For the oesophageal electrode the PNCT was similar with both stimulation techniques with mean (SE) values of 7.1 (0.2) and 6.8 (0.2) ms, respectively (pooled left and right values). However, for surface electrodes the PNCT was substantially shorter when the brachial plexus was activated (4.4 (0.1) ms) than when it was not (7.4 (0.2) ms) (mean difference 3.0 ms, 95% CI 2.7 to 3.4, p<0.0001). A small short latency CMAP was recorded from the lower chest wall electrodes during stimulation of the brachial plexus alone. CONCLUSIONS The results of this study show that lower chest wall electrodes only accurately measure PNCT when care is taken to avoid stimulating the brachial plexus. A false positive CMAP response to phrenic stimulation could be caused by inadvertent stimulation of the brachial plexus. This finding may further explain why the diaphragm CMAP recorded from chest wall electrodes can be unreliable with cervical magnetic stimulation during which brachial plexus activation occurs.

The Sleep Apnea cardioVascular Endpoints (SAVE) trial: Rationale, Ethics, Design, and Progress

ABSTRACT The Sleep Apnea cardioVascular Endpoints (SAVE) study is an ongoing investigator-initiated and conducted, international, multicenter, open, blinded endpoint, randomized controlled trial that was designed to determine whether treatment of obstructive sleep apnea (OSA) with continuous positive airways pressure (CPAP) can reduce the risk of serious cardiovascular (CV) events in patients with established CV disease (clinical trial registration NCT00738179). The results of this study will have important implications for the provision of health care to patients with sleep apnea around the world. The SAVE study has brought together respiratory, sleep, CV and stroke clinicians-scientists in an interdisciplinary collaboration with industry and government sponsorship to conduct an ambitious clinical trial. Following its launch in Australia and China in late 2008, the recruitment network expanded across 89 sites that included New Zealand, India, Spain, USA, and Brazil for a total of 2,717 patients randomized by December 2013. These patients are being followed until December 2015 so that the average length of follow-up of the cohort will be over 4 y. This article describes the rationale for the SAVE study, considerations given to the design including how various cultural and ethical challenges were addressed, and progress in establishing and maintaining the recruitment network, patient follow-up, and adherence to CPAP and procedures. The assumptions underlying the original trial sample size calculation and why this was revised downward in 2012 are also discussed. CLINICAL TRIALS REGISTRATION NUMBER NCT00738179. AUSTRALIA NEW ZEALAND CLINICAL TRIALS REGISTRY NUMBER ACTRN12608000409370.

Neural respiratory drive in patients with COPD during exercise tests.

Background: It is unknown whether neural drive is comparable in constant rate and incremental exercise tests. Few data have previously been available to address this question because of the lack of reliable methods to assess neural respiratory drive in patients with chronic obstructive pulmonary disease (COPD). Objectives: The aims of this study are to determine whether neural respiratory drive during constant rate exercise differs from that during incremental exercise and to determine whether neural respiratory drive was maximal at the end of exhaustive exercise tests. Methods: We studied sixteen patients with moderate-severe COPD (mean ± SD FEV1 29 ± 10%). Both diaphragmatic electro-myogram (EMG) and transdiaphragmatic pressure were recorded with a combined multipair electrode balloon catheter during incremental and constant (80% of maximal oxygen consumption derived from a prior incremental exercise test) treadmill exercise. Minute ventilation and oxygen uptake were also measured. Results: Root mean square (RMS) of the diaphragmatic EMG increased gradually without a plateau during incremental exercise, whereas the RMS increased initially and reached a plateau during constant work rate exercise. The RMS of the diaphragmatic EMG at the end of exercise was similar for both incremental and constant work rate exercise (176 ± 42 µV vs. 184 ± 39 µV); these values were 70 and 73% of maximal values recorded over the study. Conclusions: The pattern of increase in neural respiratory drive during incremental exercise is different to that observed during constant work rate exercise, but both exercise protocols are terminated when the patients achieve a similar but submaximal drive.