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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.

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 (SpO2 > 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 (O2) improved daytime feelings of confusion (ASV: p < 0.01; O2: p < 0.05) and fatigue (ASV: p < 0.01; O2: 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.

Sojourners to high altitude often experience poor sleep quality due to sleep‐disordered breathing. Additionally, multiple aspects of cognitive function are impaired at high altitude. However, the impact of acclimatization on sleep‐disordered breathing and whether poor sleep is a major contributor to cognitive impairments at high altitude remains uncertain. We conducted nocturnal actigraphy and polygraphy, as well as daytime cognitive function tests, in 15 participants (33% women) at sea level and over 3 days of partial acclimatization to high altitude (3800 m). Our goal was to determine if sleep‐disordered breathing improved over time and if sleep‐disordered breathing was associated with cognitive function. The apnea–hypopnea index and oxygen desaturation index increased on night 1 (adj. p = 0.026 and adj. p = 0.026, respectively), but both improved over the subsequent 2 nights. These measures were matched by poorer self‐reported sleep quality on the Stanford Sleepiness Scale and PROMIS questionnaires following 1 night at high altitude (adj. p = 0.027 and adj. p = 0.022, respectively). The reaction time on the psychomotor vigilance task was slower at high altitude and did not improve (SL: 199 ± 27, ALT1: 224 ± 33, ALT2: 216 ± 41, ALT3: 212 ± 27 ms). The reaction times on the balloon analog risk task decreased at high altitude (SL: 474 ± 235, ALT1: 375 ± 159, ALT2: 291 ± 102, ALT3: 267 ± 90 ms), perhaps indicating increased risk‐taking behavior. Finally, multiple cognitive function measures were associated with sleep‐disordered breathing and measures of subjective sleep quality, rather than low daytime arterial oxygen saturation. These data indicate that sleep‐disordered breathing at moderately high altitude improves with partial acclimatization and that some aspects of cognitive performance in unacclimatized sojourners may be impacted by poor sleep rather than hypoxemia alone. Sleep‐disordered breathing and impaired cognitive performance are common at high altitudes but the relationship between the two factors remains unclear. We found that sleep‐disordered breathing and subjective sleep quality improve over 3 days of acclimatization to 3800 m elevation. However, despite these improvements, daytime sustained attention and reaction time remained impaired.

Background High loop gain (unstable ventilatory control) is an important—but difficult to measure—contributor to obstructive sleep apnea (OSA) pathogenesis, predicting OSA sequelae and/or treatment response. Our objective was to develop and validate a clinical prediction tool of loop gain. Methods A retrospective cohort of consecutive adults with OSA (apnea–hypopnea index, AHI > 5/hour) based on in-laboratory polysomnography 01/2017–12/2018 was randomly split into a training and test-set (3:1-ratio). Using a customized algorithm (“reference standard”) loop gain was quantified from raw polysomnography signals on a continuous scale and additionally dichotomized (high > 0.7). Candidate predictors included general patient characteristics and routine polysomnography data. The model was developed (training-set) using linear regression with backward selection (tenfold cross-validated mean square errors); the predicted loop gain of the final linear regression model was used to predict loop gain class. More complex, alternative models including lasso regression or random forests were considered but did not meet pre-specified superiority-criteria. Final model performance was validated on the test-set. Results The total cohort included 1055 patients (33% high loop gain). Based on the final model, higher AHI (beta = 0.0016; P < .001) and lower hypopnea-percentage (beta = −0.0019; P < .001) predicted higher loop gain values. The predicted loop gain showed moderate-to-high correlation with the reference loop gain (r = 0.48; 95% CI 0.38–0.57) and moderate discrimination of patients with high versus low loop gain (area under the curve = 0.73; 95% CI 0.67–0.80). Conclusion To our knowledge this is the first prediction model of loop gain based on readily-available clinical data, which may facilitate retrospective analyses of existing datasets, better patient selection for clinical trials and eventually clinical practice.

Patients with chronic thromboembolic pulmonary hypertension (CTEPH) often have substantial right ventricular dysfunction. The resulting low cardiac index might predispose to sleep disordered breathing (SDB) by increasing ventilatory instability. The prevalence of SDB and potential association with impaired cardiac index was examined in patients with CTEPH. Patients referred for evaluation for pulmonary thromboendarterectomy surgery were recruited. Subjects underwent a sleep study, unless already using positive airway pressure therapy. Hemodynamic data were obtained from contemporaneous right-sided cardiac catheterization. A total of 49 subjects were included. SDB—defined as ongoing positive airway pressure use or apnea-hypopnea index (AHI) ≥5/h—was found in 57% of subjects. SDB was generally mild in severity, with respiratory events mainly consisting of hypopneas. Cardiac index was found to be significantly lower in subjects with SDB than those without (2.19 vs 2.55 L/min/m2; p = 0.024), whereas no differences were observed in other characteristics. Additionally, cardiac index was independently predictive of AHI. In a subgroup of subjects with an elevated percentage of central events, both cardiac index and lung to finger circulation time correlated with AHI. In conclusion, SDB is prevalent in patients with CTEPH and might decrease with treatments that improve cardiac index.

Obstructive and central sleep apnea affects ~1 billion people globally and may lead to serious cardiovascular and neurocognitive consequences, but treatment options are limited. High loop gain (ventilatory instability) is a major pathophysiological mechanism underlying both types of sleep apnea and can be lowered pharmacologically with acetazolamide, thereby improving sleep apnea severity. However, individual responses vary and are strongly correlated with the loop gain reduction achieved by acetazolamide. To aid with patient selection for long‐term trials and clinical care, our goal was to understand better the factors that determine the change in loop gain following acetazolamide in human subjects with sleep apnea. Thus, we (i) performed several meta‐analyses to clarify how acetazolamide affects ventilatory control and loop gain (including its primary components controller/plant gain), and based on these results, we (ii) performed physiological model simulations to assess how different baseline conditions affect the change in loop gain. Our results suggest that (i) acetazolamide primarily causes a left shift of the chemosensitivity line thus lowering plant gain without substantially affecting controller gain; and (ii) higher controller gain, higher paCO2 at eupneic ventilation, and lower CO2 production at baseline result in a more pronounced loop gain reduction with acetazolamide. In summary, the combination of mechanistic meta‐analyses with model simulations provides a unified framework of acetazolamide’s effects on ventilatory control and revealed physiological predictors of response, which are consistent with empirical observations of acetazolamide's effects in different sleep apnea subgroups. Prospective studies are needed to validate these predictors and assess their value for patient selection. (a) Based on mechanistic meta‐analyses in patients with sleep apnea, acetazolamide primarily causes a left‐shift of the chemosensitivity line thus lowering plant gain without substantially affecting controller gain; the net effect is a relative reduction in overall loop gain similar to the reduction in plant gain. (b) Based on model simulations, a higher controller gain, higher paCO2 at eupneic ventilation, and lower CO2 production at baseline each result in a more pronounced loop gain reduction with acetazolamide, and thus may predict response to acetazolamide.

The overlap syndrome (OVS), defined as coexisting chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), is linked to worse outcomes than either condition alone. Patients with COPD and OSA may have fewer obstructive events, but underlying mechanisms remain unclear. Using a large clinical cohort, we tested the hypothesis that OSA severity and pathophysiological traits differ in OVS versus OSA‐alone. Data from the SNOOzzzE cohort (3319 adults with in‐laboratory polysomnography 2017–2019) were used. OVS patients were identified through chart review and matched to OSA‐only patients (3:1) by age, sex, and body mass index. OSA severity was assessed using apnea hypopnea index (AHI), hypoxic burden (HB), and T90 (%time with SpO2 < 90%), while OSA traits were quantified from polysomnographic signals via validated algorithms. Mixed model analysis quantified group differences before and after adjustment for covariate differences (Black race, smoking) accounting for matching as a random effect. In our diverse cohort (103 OVS vs. 309 OSA‐only; 38% women, 44% non‐White, 17% Hispanic), OVS patients tended to have a lower AHI and HB (approximately −10%, p < 0.1), but significantly higher T90 (~50%, p = 0.003). OVS patients had less upper airway collapsibility, lower arousal threshold, lower ventilatory response to arousal (p < 0.05) and tended to have higher upper airway dilator muscle compensation (p = 0.09). In adjusted analyses, effect estimates were similar, but significance was attenuated. Hyperinflation and air trapping were inversely associated with AHI/HB. OSA severity and mechanisms differ in OVS versus OSA‐only. Future research should seek to evaluate these differences for their prognostic ability.

Overlap syndrome (OVS) is the concurrence of chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), and is associated with poor outcomes. We hypothesized that physiological changes in COPD may affect the pathogenesis of OSA in important ways. We therefore sought to measure the anatomical and nonanatomical OSA traits in individuals with OVS and compare to those with OSA alone. Patients with established OVS were recruited, along with age, gender, and BMI matched OSA only controls. Smoking and relevant comorbidities or medications were excluded. Subjects underwent baseline polysomnography followed by an overnight physiological research study to measure the OSA traits (Veupnea, Varousal, Vpassive, Vactive, and loop gain). Fifteen subjects with OVS and 15 matched controls with OSA alone were studied (overall 66 ± 8 years, 20% women, BMI 31 ± 4 kg/m2, apnea‐hypopnea index 49 ± 36/hr). Mixed‐modeling was used to incorporate each measurement (range 52–270 measures/trait), and account for age, gender, and BMI. There were no significant differences in the traits between OVS and OSA subjects, although OVS subjects potentially tolerated a lower ventilation before arousal (i.e., harder to wake; p = .06). Worsened lung function was significantly associated with worsened upper airway response and more unstable breathing (p < .05 for all). Consistent differences in key OSA traits were not observed between OVS and OSA alone. However, worse lung function does appear to exert an influence on several OSA traits. These findings indicate that a diagnosis of OVS should not generally influence the approach to OSA, but that lung function might be considered if utilizing OSA trait‐specific treatment. This is the first study to comprehensively measure both anatomical and non‐anatomical OSA traits during sleep in those with COPD + OSA (Overlap syndrome) and compare them to those with OSA alone. No consistent differences were found between the two groups, while worsened lung function did impact upper airway function and control of breathing. These findings have implications towards mechanisms underlying OSA, as well as management of sleep apnea.

Abstract Purpose The purpose of this article is to review the recent literature on central apnea. Sleep disordered breathing (SDB) is characterized by apneas (cessation in breathing), and hypopneas (reductions in breathing), that occur during sleep. Central sleep apnea (CSA) is sleep disordered breathing in which there is an absence or diminution of respiratory effort during breathing disturbances while asleep. In obstructive sleep apnea (OSA), on the other hand, there is an absence of flow despite ongoing ventilatory effort.Recent FindingsCentral sleep apnea is a heterogeneous disease with multiple clinical manifestations.SummaryOSA is by far the more common condition; however, CSA is highly prevalent among certain patient groups. Complex sleep apnea (CompSA) is defined as the occurrence/emergence of CSA upon treatment of OSA. Similarly, there is considerable overlap between CSA and OSA in pathogenesis as well as impacts. Thus, understanding sleep disordered breathing is important for many practicing clinicians.

There is a need for alternatives to positive airway pressure for the treatment of obstructive sleep apnea and snoring. Improving upper airway dilator function might alleviate upper airway obstruction. We hypothesized that transoral neuromuscular stimulation would reduce upper airway collapse in concert with improvement in genioglossal muscle function. Subjects with simple snoring and mild OSA (AHI < 15/h on screening) underwent in‐laboratory polysomnography with concurrent genioglossal electromyography (EMGgg) before and after 4–6 weeks of twice‐daily transoral neuromuscular stimulation. Twenty patients completed the study: Sixteen males, mean ± SD age 40 ± 13 years, and BMI 26.3 ± 3.8 kg/m2. Although there was no change in non‐rapid eye movement EMGgg phasic (p = 0.66) or tonic activity (p = 0.83), and no decrease in snoring or flow limitation, treatment was associated with improvements in tongue endurance, sleep quality, and sleep efficiency. In this protocol, transoral neurostimulation did not result in changes in genioglossal activity or upper airway collapse, but other beneficial effects were noted suggesting a need for additional mechanistic investigation. Daytime transoral neuromuscular stimulation is a novel treatment for mild obstructive sleep apnea and snoring. We sought to evaluate the mechanism by which this method of sleep apnea improves disease severity. There was no change in neural drive to genioglossus, but there was an improvement in tongue endurance.