Background: Noninvasive ventilation (NIV) is used for patients with chronic obstructive pulmonary disease (COPD) and chronic hypercapnia. However, evidence for clinical efficacy and optimal management of therapy is limited. Target Audience: Patients with COPD, clinicians who care for them, and policy makers. Methods: We summarized evidence addressing five PICO (patients, intervention, comparator, and outcome) questions. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to evaluate the certainty in evidence and generate actionable recommendations. Recommendations were formulated by a panel of pulmonary and sleep physicians, respiratory therapists, and methodologists using the Evidence-to-Decision framework. Conclusions: This expert panel provides evidence-based recommendations addressing the use of NIV in patients with COPD and chronic stable hypercapnic respiratory failure.

Central sleep apnoea (CSA)—the temporary absence or diminution of ventilator effort during sleep—is seen in a variety of forms including periodic breathing in infancy and healthy adults at altitude and Cheyne-Stokes respiration in heart failure. In most circumstances, the cyclic absence of effort is paradoxically a consequence of hypersensitive ventilatory chemoreflex responses to oppose changes in airflow, i.e. elevated loop gain, leading to overshoot/undershoot ventilatory oscillations. Considerable evidence illustrates overlap between CSA and obstructive sleep apnoea (OSA), including elevated loop gain in patients with OSA and the presence of pharyngeal narrowing during central apnoeas. Indeed, treatment of OSA, whether via CPAP, tracheostomy, or oral appliances, can reveal CSA, an occurrence referred to as complex sleep apnoea. Factors influencing loop gain include increased chemosensitivity (increased controller gain), reduced damping of blood gas levels (increased plant gain) and increased lung to chemoreceptor circulatory delay. Sleep-wake transitions and pharyngeal dilator muscle responses effectively raise the controller gain and therefore also contribute to total loop gain and overall instability. In some circumstances, for example apnoea of infancy and central congenital hypoventilation syndrome, central apnoeas are the consequence of ventilatory depression and defective ventilatory responses, i.e. low loop gain. The efficacy of available treatments for CSA can be explained in terms of their effects on loop gain, e.g. CPAP improves lung volume (plant gain), stimulants reduce the alveolar-inspired PCO2 difference, supplemental oxygen lowers chemosensitivity. Understanding the magnitude of loop gain and the mechanisms contributing to instability may facilitate personalised interventions for CSA.

The clinical presentation of COVID‐19 due to infection with SARS‐CoV‐2 is highly variable with the majority of patients having mild symptoms while others develop severe respiratory failure. The reason for this variability is unclear but is in critical need of investigation. Some COVID‐19 patients have been labelled with ‘happy hypoxia’, in which patient complaints of dyspnoea and observable signs of respiratory distress are reported to be absent. Based on ongoing debate, we highlight key respiratory and neurological components that could underlie variation in the presentation of silent hypoxaemia and define priorities for subsequent investigation.

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 (220.3 vs. 219.3 cm H 2 O, 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).

Obstructive sleep apnoea is a common disease that is now more widely recognised because of the rise in prevalence and the increasingly compelling data that shows major neurocognitive and cardiovascular sequelae. At the same time, the clinical practice of sleep medicine is changing rapidly, with novel diagnostics and treatments that have established a home-based (rather than laboratory-based) management approach. We review the most recent insights and discoveries in obstructive sleep apnoea, with a focus on diagnostics and therapeutics. As will be discussed, management of obstructive sleep apnoea could soon transition from a so-called one size fits all approach to an individualised approach.

ClinicalTrials.Gov; Title: The Impact of Sleep Apnea Treatment on Physiology Traits in Chinese Patients With Obstructive Sleep Apnea; Identifier: NCT02696629; URL: https://clinicaltrials.gov/show/NCT02696629.

Impairments in cognitive function, mood, and sleep quality occur following ascent to high altitude. Low oxygen (hypoxia) and poor sleep quality are both linked to impaired cognitive performance, but their independent contributions at high altitude remain unknown. Adaptive servoventilation (ASV) improves sleep quality by stabilizing breathing and preventing central apneas without supplemental oxygen. We compared the efficacy of ASV and supplemental oxygen sleep treatments for improving daytime cognitive function and mood in high-altitude visitors (N = 18) during acclimatization to 3,800 m. Each night, subjects were randomly provided with ASV, supplemental oxygen (SpO 2 > 95%), or no treatment. Each morning subjects completed a series of cognitive function tests and questionnaires to assess mood and multiple aspects of cognitive performance. We found that both ASV and supplemental oxygen (O 2 ) improved daytime feelings of confusion (ASV: p < 0.01; O 2 : p < 0.05) and fatigue (ASV: p < 0.01; O 2 : p < 0.01) but did not improve other measures of cognitive performance at high altitude. However, performance improved on the trail making tests (TMT) A and B (p < 0.001), the balloon analog risk test (p < 0.0001), and the psychomotor vigilance test (p < 0.01) over the course of three days at altitude after controlling for effects of sleep treatments. Compared to sea level, subjects reported higher levels of confusion (p < 0.01) and performed worse on the TMT A (p < 0.05) and the emotion recognition test (p < 0.05) on nights when they received no treatment at high altitude. These results suggest that stabilizing breathing (ASV) or increasing oxygenation (supplemental oxygen) during sleep can reduce feelings of fatigue and confusion, but that daytime hypoxia may play a larger role in other cognitive impairments reported at high altitude. Furthermore, this study provides evidence that some aspects of cognition (executive control, risk inhibition, sustained attention) improve with acclimatization.

IntroductionAcetazolamide (AZM) is used for various conditions (eg, altitude sickness, sleep apnoea, glaucoma), but therapy is often limited by its side effect profile. Our objective was to estimate the risk of commonly reported side effects based on meta-analyses. We hypothesised that these risks are dose-dependent.MethodsWe queried MEDLINE/EMBASE (Medical Literature Analysis and Retrieval System Online/Excerpta Medica dataBASE) up until 04/10/2019, including any randomised placebo-controlled trial in which adults received oral AZM versus placebo reporting side effects. Eligibility assessment was performed by two independent reviewers. Data were abstracted by one reviewer who verified key entries at a second time point. For side effects reported by >3 studies a pooled effect estimate was calculated, and heterogeneity assessed via I2; for outcomes reported by >5 studies effect modification by total daily dose (EMbyTDD; <400 mg/d, 400–600 mg/d, >600 mg/d) was assessed via meta-regression. For pre-specified, primary outcomes (paraesthesias, taste disturbances, polyuria and fatigue) additional subgroup analyses were performed using demographics, intervention details, laboratory changes and risk of bias.ResultsWe included 42 studies in the meta-analyses (Nsubjects=1274/1211 in AZM/placebo groups). AZM increased the risk of all primary outcomes (p<0.01, I2 ≤16% and low-to-moderate quality of evidence for all)—the numbers needed to harm (95% CI; nStudies) for each were: paraesthesias 2.3 (95% CI 2 to 2.7; n=39), dysgeusia 18 (95% CI 10 to 38, n=22), polyuria 17 (95% CI 9 to 49; n=22), fatigue 11 (95% CI 6 to 24; n=14). The risk for paraesthesias (beta=1.8 (95% CI 1.1 to 2.9); PEMbyTDD=0.01) and dysgeusia (beta=3.1 (95% CI 1.2 to 8.2); PEMbyTDD=0.02) increased with higher AZM doses; the risk of fatigue also increased with higher dose but non-significantly (beta=2.6 (95% CI 0.7 to 9.4); PEMbyTDD=0.14).DiscussionThis comprehensive meta-analysis of low-to-moderate quality evidence defines risk of common AZM side effects and corroborates dose dependence of some side effects. These results may inform clinical decision making and support efforts to establish the lowest effective dose of AZM for various conditions.