Combination pharmacological therapy targeting multiple mechanisms of sleep apnoea: a randomised controlled cross-over trial.

RATIONALE: Acetazolamide and atomoxetine-plus-oxybutynin ('AtoOxy') can improve obstructive sleep apnoea (OSA) by stabilising ventilatory control and improving dilator muscle responsiveness respectively. Given the different pathophysiological mechanisms targeted by each intervention, we tested whether AtoOxy-plus-acetazolamide would be more efficacious than AtoOxy alone. METHODS: In a multicentre randomised crossover trial, 19 patients with moderate-to-severe OSA received AtoOxy (80/5 mg), acetazolamide (500 mg), combined AtoOxy-plus-acetazolamide or placebo at bedtime for three nights (half doses on first night) with a 4-day washout between conditions. Outcomes were assessed at baseline and night 3 of each treatment period. Mixed model analysis compared the reduction in Apnoea-Hypopnoea Index (AHI) from baseline between AtoOxy-plus-acetazolamide and AtoOxy (primary outcome). Secondary outcomes included hypoxic burden and arousal index. RESULTS: Although AtoOxy lowered AHI by 49 (33, 62)%baseline (estimate (95% CI)) vs placebo, and acetazolamide lowered AHI by+34 (14, 50)%baseline vs placebo, AtoOxy-plus-acetazolamide was not superior to AtoOxy alone (difference: -2 (-18, 11)%baseline, primary outcome p=0.8). Likewise, the hypoxic burden was lowered with AtoOxy (+58 (37, 71)%baseline) and acetazolamide (+37 (5, 58)%baseline), but no added benefit versus AtoOxy occurred when combined (difference: -13 (-5, 39)%baseline). Arousal index was also modestly reduced with each intervention (11%baseline-16%baseline). Mechanistic analyses revealed that similar traits (ie, higher baseline compensation, lower loop gain) were associated with both AtoOxy and acetazolamide efficacy. CONCLUSIONS: While AtoOxy halved AHI, and acetazolamide lowered AHI by a third, the combination of these leading experimental interventions provided no greater efficacy than AtoOxy alone. Failure of acetazolamide to further increase efficacy suggests overlapping physiological mechanisms. TRIAL REGISTRATION NUMBER: NCT03892772.

Is snoozing losing? Why intermittent morning alarms are used and how they affect sleep, cognition, cortisol, and mood.

Pressing the snooze button is a common way to start the day, but little is known about this behaviour. Through two studies we determined predictors and effects of snoozing. In Study 1 (n = 1732) respondents described their waking habits, confirming that snoozing is widespread, especially in younger individuals and later chronotypes. Morning drowsiness and shorter sleep were also more common for those who snooze. Study 2 was a within-subjects laboratory study (with polysomnography) on habitual snoozers (n = 31), showing that 30 min of snoozing improved or did not affect performance on cognitive tests directly upon rising compared to an abrupt awakening. Bayes factors indicate varying strengths of this evidence. Snoozing resulted in about 6 min of lost sleep, while preventing awakenings from slow-wave sleep (N3). There were no clear effects of snoozing on the cortisol awakening response, morning sleepiness, mood, or overnight sleep architecture. A brief snooze period may thus help alleviate sleep inertia, without substantially disturbing sleep, for late chronotypes and those with morning drowsiness.

Fit-Tested N95 Masks Combined With Portable High-Efficiency Particulate Air Filtration Can Protect Against High Aerosolized Viral Loads Over Prolonged Periods at Close Range.

BACKGROUND: Healthcare workers (HCWs) are at risk from aerosol transmission of severe acute respiratory syndrome coronavirus 2. The aims of this study were to (1) quantify the protection provided by masks (surgical, fit-testFAILED N95, fit-testPASSED N95) and personal protective equipment (PPE), and (2) determine if a portable high-efficiency particulate air (HEPA) filter can enhance the benefit of PPE. METHODS: Virus aerosol exposure experiments using bacteriophage PhiX174 were performed. An HCW wearing PPE (mask, gloves, gown, face shield) was exposed to nebulized viruses (108 copies/mL) for 40 minutes in a sealed clinical room. Virus exposure was quantified via skin swabs applied to the face, nostrils, forearms, neck, and forehead. Experiments were repeated with a HEPA filter (13.4 volume-filtrations/hour). RESULTS: Significant virus counts were detected on the face while the participants were wearing either surgical or N95 masks. Only the fit-testPASSED N95 resulted in lower virus counts compared to control (P = .007). Nasal swabs demonstrated high virus exposure, which was not mitigated by the surgical/fit-testFAILED N95 masks, although there was a trend for the fit-testPASSED N95 mask to reduce virus counts (P = .058). HEPA filtration reduced virus to near-zero levels when combined with fit-testPASSED N95 mask, gloves, gown, and face shield. CONCLUSIONS: N95 masks that have passed a quantitative fit-test combined with HEPA filtration protects against high virus aerosol loads at close range and for prolonged periods of time.

Examining the impact of multilevel upper airway surgery on the obstructive sleep apnoea endotypes and their utility in predicting surgical outcomes.

BACKGROUND AND OBJECTIVE: Upper airway surgery for obstructive sleep apnoea (OSA) is an alternative treatment for patients who are intolerant of continuous positive airway pressure (CPAP). However, upper airway surgery has variable treatment efficacy with no reliable predictors of response. While we now know that there are several endotypes contributing to OSA (i.e., upper airway collapsibility, airway muscle response/compensation, respiratory arousal threshold and loop gain), no study to date has examined: (i) how upper airway surgery affects all four OSA endotypes, (ii) whether knowledge of baseline OSA endotypes predicts response to surgery and (iii) whether there are any differences when OSA endotypes are measured using the CPAP dial-down or clinical polysomnographic (PSG) methods. METHODS: We prospectively studied 23 OSA patients before and ≥3 months after multilevel upper airway surgery. Participants underwent clinical and research PSG to measure OSA severity (apnoea-hypopnoea index [AHI]) and endotypes (measured in supine non-rapid eye movement [NREM]). Values are presented as mean ± SD or median (interquartile range). RESULTS: Surgery reduced the AHITotal (38.7 [23.4 to 79.2] vs. 22.0 [13.3 to 53.5] events/h; p = 0.009). There were no significant changes in OSA endotypes, however, large but variable improvements in collapsibility were observed (CPAP dial-down method: ∆1.9 ± 4.9 L/min, p = 0.09, n = 21; PSG method: ∆3.4 [-2.8 to 49.0]%Veupnoea , p = 0.06, n = 20). Improvement in collapsibility strongly correlated with improvement in AHI (%∆AHISupineNREM vs. ∆collapsibility: p < 0.005; R2  = 0.46-0.48). None of the baseline OSA endotypes predicted response to surgery. CONCLUSION: Surgery unpredictably alters upper airway collapsibility but does not alter the non-anatomical endotypes. There are no baseline predictors of response to surgery.

Viable virus aerosol propagation by positive airway pressure circuit leak and mitigation with a ventilated patient hood.

INTRODUCTION: Nosocomial transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a major feature of the COVID-19 pandemic. Evidence suggests patients can auto-emit aerosols containing viable viruses; these aerosols could be further propagated when patients undergo certain treatments, including continuous positive airway pressure (PAP) therapy. Our aim was to assess 1) the degree of viable virus propagated from PAP circuit mask leak and 2) the efficacy of a ventilated plastic canopy to mitigate virus propagation. METHODS: Bacteriophage phiX174 (108 copies·mL-1) was nebulised into a custom PAP circuit. Mask leak was systematically varied at the mask interface. Plates containing Escherichia coli host quantified viable virus (via plaque forming unit) settling on surfaces around the room. The efficacy of a low-cost ventilated headboard created from a tarpaulin hood and a high-efficiency particulate air (HEPA) filter was tested. RESULTS: Mask leak was associated with virus contamination in a dose-dependent manner (χ2=58.24, df=4, p<0.001). Moderate mask leak (≥21 L·min-1) was associated with virus counts equivalent to using PAP with a vented mask. The highest frequency of viruses was detected on surfaces <1 m away; however, viable viruses were recorded up to 3.86 m from the source. A plastic hood with HEPA filtration significantly reduced viable viruses on all plates. HEPA exchange rates ≥170 m3·h-1 eradicated all evidence of virus contamination. CONCLUSIONS: Mask leak from PAP may be a major source of environmental contamination and nosocomial spread of infectious respiratory diseases. Subclinical mask leak levels should be treated as an infectious risk. Low-cost patient hoods with HEPA filtration are an effective countermeasure.

A consensus opinion amongst stakeholders as to benefits of obstructive sleep apnoea treatment for cardiovascular health.

BACKGROUND AND OBJECTIVE: Obstructive sleep apnoea (OSA) is a prevalent sleep disorder associated with increased cardiovascular morbidity and mortality. Whether treatment of OSA improves cardiovascular risk remains controversial. Our aim was to determine a consensus opinion of key sleep medicine stakeholder groups as to the cardiovascular benefits of treating moderate-severe OSA. METHODS: A multidisciplinary panel was assembled from representatives from the Australasian Sleep Association, Sleep Health Foundation, Australasian Sleep Technologists Association, the Sleep Health Foundation Business Council and the Sleep Disorders Australia patient support group. Three statements reflecting areas of controversy related to cardiovascular benefits of OSA treatment were created. A modified RAND/UCLA appropriateness methodology was applied determining the panel's level of consensus and agreement with each statement. RESULTS: Voting results indicated the panel: (1) remained unsure whether moderate-severe OSA treatment improves rates of cardiovascular events/death, (2) agreed that moderate-severe OSA treatment improves blood pressure in patients with hypertension and (3) mostly agreed that moderate-severe OSA treatment improves left ventricular function in patients with heart failure. Consensus of opinion was achieved for statements (1) and (2), but was narrowly missed for statement (3). CONCLUSION: The panel believed that findings from large-scale randomized trials indicate that treatment of moderate-severe OSA has not been established to improve cardiovascular event or morbidity/mortality rates. Strong evidence supports the ability of treatment to reduce blood pressure. Whilst many panel members believed that treatment improves left ventricular function, some were uncertain of the clinical significance of this secondary endpoint measure derived from lesser quality evidence.

Response to a combination of oxygen and a hypnotic as treatment for obstructive sleep apnoea is predicted by a patient's therapeutic CPAP requirement.

BACKGROUND AND OBJECTIVE: Upper airway collapsibility predicts the response to several non-continuous positive airway pressure (CPAP) interventions for obstructive sleep apnoea (OSA). Measures of upper airway collapsibility cannot be easily performed in a clinical context; however, a patient's therapeutic CPAP requirement may serve as a surrogate measure of collapsibility. The present work aimed to compare the predictive use of CPAP level with detailed physiological measures of collapsibility. METHODS: Therapeutic CPAP levels and gold-standard pharyngeal collapsibility measures (passive pharyngeal critical closing pressure (Pcrit ) and ventilation at CPAP level of 0 cmH2 O (Vpassive )) were retrospectively analysed from a randomized controlled trial (n = 20) comparing the combination of oxygen and eszopiclone (treatment) versus placebo/air control. Responders (9/20) to treatment were defined as those who exhibited a 50% reduction in apnoea/hypopnoea index (AHI) plus an AHI<15 events/h on-therapy. RESULTS: Responders to treatment had a lower therapeutic CPAP requirement compared with non-responders (6.6 (5.4-8.1) cmH2 O vs 8.9 (8.4-10.4) cmH2 O, P = 0.007), consistent with their reduced collapsibility (lower Pcrit , P = 0.017, higher Vpassive P = 0.025). Therapeutic CPAP level provided the highest predictive accuracy for differentiating responders from non-responders (area under the curve (AUC) = 0.86 ± 0.9, 95% CI: 0.68-1.00, P = 0.007). However, both Pcrit (AUC = 0.83 ± 0.11, 95% CI: 0.62-1.00, P = 0.017) and Vpassive (AUC = 0.77 ± 0.12, 95% CI: 0.53-1.00, P = 0.44) performed well, and the difference in AUC for these three metrics was not statistically different. A therapeutic CPAP level ≤8 cmH2 O provided 78% sensitivity and 82% specificity (positive predictive value = 78%, negative predictive value = 82%) for predicting a response to these therapies. CONCLUSION: Therapeutic CPAP requirement, as a surrogate measure of pharyngeal collapsibility, predicts the response to non-anatomical therapy (oxygen and eszopiclone) for OSA.

Dynamic loop gain increases upon adopting the supine body position during sleep in patients with obstructive sleep apnoea.

BACKGROUND AND OBJECTIVE: Obstructive sleep apnoea (OSA) is typically worse in the supine versus lateral sleeping position. One potential factor driving this observation is a decrease in lung volume in the supine position which is expected by theory to increase a key OSA pathogenic factor: dynamic ventilatory control instability (i.e. loop gain). We aimed to quantify dynamic loop gain in OSA patients in the lateral and supine positions, and to explore the relationship between change in dynamic loop gain and change in lung volume with position. METHODS: Data from 20 patients enrolled in previous studies on the effect of body position on OSA pathogenesis were retrospectively analysed. Dynamic loop gain was calculated from routinely collected polysomnographic signals using a previously validated mathematical model. Lung volumes were measured in the awake state with a nitrogen washout technique. RESULTS: Dynamic loop gain was significantly higher in the supine than in the lateral position (0.77 ± 0.15 vs 0.68 ± 0.14, P = 0.012). Supine functional residual capacity (FRC) was significantly lower than lateral FRC (81.0 ± 15.4% vs 87.3 ± 18.4% of the seated FRC, P = 0.021). The reduced FRC we observed on moving to the supine position was predicted by theory to increase loop gain by 10.2 (0.6, 17.1)%, a value similar to the observed increase of 8.4 (-1.5, 31.0)%. CONCLUSION: Dynamic loop gain increased by a small but statistically significant amount when moving from the lateral to supine position and this may, in part, contribute to the worsening of OSA in the supine sleeping position.