Pathogenesis of sleep disordered breathing in the setting of opioid use: A multiple mediation analysis using physiology.

STUDY OBJECTIVES: Opioid medications are commonly used and are known to impact both breathing and sleep, and are linked with adverse health outcomes including death. Clinical data indicate that chronic opioid use causes central sleep apnea, and might also worsen obstructive sleep apnea. The mechanisms by which opioids influence sleep-disordered breathing pathogenesis are not established. METHODS: Patients who underwent clinically-indicated polysomnography confirming sleep-disordered breathing (SDB) (AHI≥5/hr) were included. Each patient using opioids was matched by sex, age, and BMI to three control individuals not using opioids. Physiology known to influence SDB pathogenesis were determined from validated polysomnography-based signal analysis. PSG and physiology paramters of interest were compared between opioid and control individuals, adjusted for covariates. Mediation analysis was used to evaluate the link between opioids, physiology, and polysomnographic metrics. RESULTS: 178 individuals using opioids were matched to 534 controls (median [IQR] age 59 [50,65] years, BMI 33 [29,41] kg/m2, 57% female, daily morphine equivalent 30 [20,80] mg). Compared with controls, opioids were associated with increased central apneas (2.8 vs 1.7 events/hr; p=0.001) and worsened hypoxemia (5 vs 3% sleep with SpO2<88%; p=0.013), with similar overall AHI. Use of opioids was associated with higher loop gain, a lower respiratory rate and higher respiratory rate variability. Higher loop gain and increased respiratory rate variability mediated the effect of opioids on central apnea, but did not mediate the effect on hypoxemia. CONCLUSIONS: Opioids have multi-level effects impacting SDB. Targeting these factors may help mitigate deleterious respiratory consequences of chronic opioid use.

The Effect of Obesity on Sleep Apnea Pathogenesis Differs in Women vs Men: Multiple Mediation Analyses in the Retrospective SNOOzzzE Cohort.

BACKGROUND AND OBJECTIVE: There are multiple mechanisms underlying obstructive sleep apnea (OSA) development. However, how classic OSA risk factors such as body mass index (BMI) and sex portend to OSA development have not been fully described. Thus, we sought to evaluate how obesity leads to OSA, and assess how these mechanisms differ between men and women. Methods The San Diego Multi-Outcome OSA Endophenotype (SNOOzzzE) cohort includes 3,319 consecutive adults who underwent a clinical in-laboratory polysomnography at the UCSD sleep clinic between 1/2017-12/2019. Using routine polysomnography signals, we determined OSA endotypes. We then performed mediation analyses stratified by sex to determine how BMI influenced apnea hypopnea index (AHI) using OSA endotypic traits as mediators. Results We included 2,146 patients of whom 919 (43%) were women and 1,227 (57%) were obese. BMI was significantly associated with AHI in both women and men. In men, the effect of BMI on AHI was partially mediated by a reduction in upper airway stiffness (31% of total effect, TE), by a reduction in circulatory delay (16%TE), and by an increase in arousal threshold (7%TE). In women, the effect of BMI on AHI was partially mediated by a reduction in circulatory delay (22%TE). Discussion BMI-related OSA pathogenesis differs by sex. An increase in upper airway collapsibility (in men) is consistent with prior studies. A reduction in circulatory delay may lead to shorter and thus more events per hour (i.e., higher AHI), while the association between a higher arousal threshold and higher AHI may reflect reverse causation.

Loop Gain as a Predictor of Blood Pressure Response in Patients Treated for Obstructive Sleep Apnea: Secondary Analysis of a Clinical Trial.

Rationale: Randomized trials have shown inconsistent cardiovascular benefits from obstructive sleep apnea (OSA) therapy. Intermittent hypoxemia can increase both sympathetic nerve activity and loop gain ("ventilatory instability"), which may thus herald cardiovascular treatment benefit. Objectives: To test the hypothesis that loop gain predicts changes in 24-hour mean blood pressure (MBP) in response to OSA therapy and compare its predictive value against that of other novel biomarkers. Methods: The HeartBEAT (Heart Biomarker Evaluation in Apnea Treatment) trial assessed the effect of 12 weeks of continuous positive airway pressure (CPAP) versus oxygen versus control on 24-hour MBP. We measured loop gain and hypoxic burden from sleep tests and identified subjects with a sleepy phenotype using cluster analysis. Associations between biomarkers and 24-h MBP were assessed in the CPAP/oxygen arms using linear regression models adjusting for various covariates. Secondary outcomes and predictors were analyzed similarly. Results: We included 93 and 94 participants in the CPAP and oxygen arms, respectively. Overall, changes in 24-hour MBP were small, but interindividual variability was substantial (mean [standard deviation], -2 [8] and 1 [8] mm Hg in the CPAP and oxygen arms, respectively). Higher loop gain was significantly associated with greater reductions in 24-hour MBP independent of covariates in the CPAP arm (-1.5 to -1.9 mm Hg per 1-standard-deviation increase in loop gain; P ⩽ 0.03) but not in the oxygen arm. Other biomarkers were not associated with improved cardiovascular outcomes. Conclusions: To our knowledge, this is the first study suggesting that loop gain predicts blood pressure response to CPAP therapy. Eventually, loop gain estimates may facilitate patient selection for research and clinical practice. Clinical trial registered with www.clinicaltrials.gov (NCT01086800).

Effectiveness of long-term noninvasive ventilation measured by remote monitoring in neuromuscular disease.

Background and objective: Patients with neuromuscular disease are often treated with home noninvasive ventilation (NIV) with devices capable of remote patient monitoring. We sought to determine whether long-term NIV data could provide insight into the effectiveness of ventilation over time. Methods: We abstracted available longitudinal data for adults with neuromuscular disease in monthly increments from first available to most recent. Generalised linear mixed-effects modelling with subject-level random effects was used to evaluate trajectories over time. Results: 1799 months of data across 85 individuals (median age 61, interquartile range (IQR) 46-71 years; 44% female; 49% amyotrophic lateral sclerosis (ALS)) were analysed, with a median (IQR) of 17 (8-35) months per individual. Over time, tidal volume increased and respiratory rate decreased. Dynamic respiratory system compliance decreased, accompanied by increased pressure support. Compared to volume-assured mode, fixed-pressure modes were associated with lower initial tidal volume, higher respiratory rate and lower pressures, which did not fully equalise with volume-assured mode over time. Compared with non-ALS patients, those with ALS had lower initial pressure support, but faster increases in pressure support over time, and ALS was associated wtih a more robust increase in respiratory rate in response to low tidal volume. Nonsurvivors did not differ from survivors in ventilatory trajectories over time, but did exhibit decreasing NIV use prior to death, in contrast with stable use in survivors. Conclusion: NIV keeps breathing patterns stable over time, but support needs are dynamic and influenced by diagnosis and ventilation mode. Mortality is preceded by decreased NIV use rather than inadequate support during use.

The Impact of Underlying Obstructive Sleep Apnea Treatment on Exercise Capacity in Patients With Pulmonary Hypertension Undergoing a Cardiac Rehabilitation Program.

PURPOSE: Obstructive sleep apnea (OSA)-related pulmonary hypertension (PH) can often be reversed with treatment of OSA via continuous positive airway pressure. We hypothesized that treatment of OSA would be associated with a greater improvement in exercise capacity (EC) with cardiac rehabilitation (CR), especially in patients with PH as compared with those who are untreated. METHODS: We reviewed medical records of 315 consecutive patients who participated in CR. Pulmonary hypertension status was assessed on the basis of peak tricuspid regurgitant velocity (>2.8 m/sec) on pre-CR echocardiograms. The OSA status (no, untreated, or treated OSA) was determined on the basis of results from sleep studies, continuous positive airway pressure device data, and physician notes. Exercise capacity was assessed by measuring metabolic equivalents (METs) using a treadmill stress test before and after CR. RESULTS: We included 290 patients who participated in CR with available echocardiographic data: 44 (15%) had PH, and 102 (35%) had known OSA (30 treated and 72 untreated). Patients with OSA versus those with no OSA were more likely to have PH ( P = .06). Patients with PH versus no-PH were associated with significantly lower baseline METs in crude and adjusted analyses ( P ≤. 004). The PH and OSA status in isolation were not associated with changes in METs ( P > .2) with CR. There was a significant interaction between OSA treatment and PH in crude and adjusted analyses ( P ≤.01): treatment vs no treatment of OSA was associated with a clinically and statistically greater improvement in METs in patients who participated in CR with but not without PH. CONCLUSION: Baseline PH was associated with decreased baseline EC but did not attenuate CR-related improvements in METs. However, in the subset of OSA patients with PH, OSA therapy was associated with improved EC after CR.

The impact of daytime transoral neuromuscular stimulation on upper airway physiology - A mechanistic clinical investigation.

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.

Obesity Hypoventilation Syndrome and Postsurgical Outcomes in a Bariatric Surgery Cohort.

PURPOSE: Patients with obesity and elevated serum bicarbonate suggesting obesity hypoventilation syndrome (OHS) undergoing bariatric surgery may represent a unique subgroup. Information regarding surgical outcomes in this population remains limited. We sought to test the hypothesis that an elevated bicarbonate would be an important predictor of perioperative complications (i.e., length of hospital stay) and postsurgical outcomes (i.e., weight loss at 1 year). MATERIALS AND METHODS: Consecutive patients undergoing bariatric surgery between January 2015 and December 2018 were included. Patients with a preoperative serum bicarbonate ≥ 27 mEq/L were classified as suspected OHS. RESULTS: Of 297 patients, the prevalence of suspected OHS based on an elevated bicarbonate was 19.5% (95% CI: 15.3 to 24.6%). Length of hospital stay was similar in the suspected OHS and non-OHS control group (1.50 vs 1.49 days, P = 0.98). The achieved weight loss from peak preoperative weight to 1 year post-surgery was less in the suspected OHS vs the control group (4.2% [95% CI 1.6 to 6.8]; P = 0.002). CONCLUSION: Patients with serum bicarbonate ≥ 27 mEq/L as a surrogate marker for OHS experienced weight loss that was significantly less than their normal serum bicarbonate counterparts, but still achieved weight loss deemed clinically important by current guidelines. We observed no significant difference in length of hospital stay at time of surgery.

Point-of-care prediction model of loop gain in patients with obstructive sleep apnea: development and validation.

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.

Diagnostic performance of screening tools for the detection of obstructive sleep apnea in people living with HIV.

STUDY OBJECTIVES: Many people living with human immunodeficiency virus (PLWH) have undiagnosed obstructive sleep apnea (OSA), which may contribute to commonly reported fatigue and the high cardiovascular disease burden in this population. Our objective was to assess the utility of traditional OSA screening tools (STOP-BANG, Berlin Questionnaire, and Epworth Sleepiness Scale) for detecting OSA in PLWH. METHODS: Adult PLWH were recruited from sleep/ human immunodeficiency virus clinics and the community into a larger clinical trial that included completion of these questionnaires before in-laboratory polysomnography. Discriminatory performance of these screening tools was assessed using area under receiver operating characteristic curves (AUC). The reference standard for the primary analysis was OSA based on an apnea-hypopnea index ≥ 5 events/h using recommended "1A"-criteria (hypopnea with 3% desaturation and/or arousal). Secondary analyses explored acceptable "1B"-criteria (hypopnea with 4% desaturation) and/or higher apnea-hypopnea index cut-offs (≥ 15 events/h). RESULTS: 120 PLWH were included (mean age: 50 ± 11 years; body mass index: 27 ± 4 kg/m2, 84% male) and OSA was diagnosed in 75% using 1A-criteria. In the primary analysis, the discriminatory performance of the 3 screening tools was low (AUCs 0.58 to 0.70) and similar across the tools (P ≥ .14). In secondary analyses, STOP-BANG showed moderate-high discriminatory ability (AUCs 0.77-0.80) and performed significantly better (P ≤ .008) than the Berlin Questionnaire or Epworth Sleepiness Scale (AUCs 0.53-0.62). CONCLUSIONS: OSA was highly prevalent in our cohort of PLWH. Although STOP-BANG could reasonably identify moderate-severe OSA, the tools were not reliable for mild disease. Specifically, the questionnaires perform poorly for PLWH with mild OSA manifesting with arousals, yet such people may be at risk of fatigue/sleepiness and impaired memory consolidation. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: Obstructive Sleep Apnea Endotypes and Impact on Phenotypes of People Living with HIV (PLWH/OSA); Identifier: NCT03575143; URL: https://clinicaltrials.gov/ct2/show/NCT03575143. CITATION: Schmickl CN, Bosompra N-O, DeYoung PN, et al. Diagnostic performance of screening tools for the detection of obstructive sleep apnea in people living with HIV. J Clin Sleep Med. 2022;18(7):1797-1804.

Pathogenesis of obstructive sleep apnea in people living with HIV.

Obstructive sleep apnea (OSA) is highly prevalent in people living with human immunodeficiency virus (HIV) (PLWH), and it might contribute to frequently reported symptoms and comorbidities. Traditional risk factors for OSA are often absent in PLWH, suggesting that HIV or HIV medications might predispose to OSA. Therefore, we measured the anatomical and nonanatomical traits important for OSA pathogenesis in those with and without HIV. We recruited virally suppressed PLWH who had been previously diagnosed with OSA (PLWH + OSA) adherent to positive airway pressure (PAP) therapy, along with age-, sex-, and body mass index (BMI)-matched OSA controls. All participants underwent a baseline polysomnogram to assess OSA severity and a second overnight research sleep study during which the airway pressure was adjusted slowly or rapidly to measure the OSA traits. Seventeen PLWH + OSA and 17 OSA control participants were studied [median age = 58 (IQR = 54-65) yr, BMI = 30.7 (28.4-31.8) kg/m2, apnea-hypopnea index = 46 (24-74)/h]. The groups were similar, although PLWH + OSA demonstrated greater sleepiness (despite PAP) and worse sleep efficiency on baseline polysomnography. On physiological testing during sleep, there were no statistically significant differences in OSA traits (including Veupnea, Varousal, Vpassive, Vactive, and loop gain) between PLWH + OSA and OSA controls, using mixed-effects modeling to account for age, sex, and BMI and incorporating each repeated measurement (range = 72-334 measures/trait). Our data suggest that well-treated HIV does not substantially impact the pathogenesis of OSA. Given similar underlying physiology, existing available therapeutic approaches are likely to be adequate to manage OSA in PLWH, which might improve symptoms and comorbidities.NEW & NOTEWORTHY Clinical data suggest an increased risk of obstructive sleep apnea (OSA) in people living with HIV (PLWH), while OSA might account for chronic health issues in this population. We characterized the anatomical and nonanatomical OSA traits in PLWH + OSA compared with OSA controls, using detailed physiological measurements obtained during sleep. Our data suggest against a major impact of HIV on OSA pathogenesis. Available OSA management strategies should be effective to address this potentially important comorbidity in PLWH.

Effects of acetazolamide on control of breathing in sleep apnea patients: Mechanistic insights using meta-analyses and physiological model simulations.

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.

Silent hypoxaemia in COVID-19 patients.

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.

Screening for Obstructive Sleep Apnea in a Diverse Bariatric Surgery Population.

OBJECTIVE: Obstructive sleep apnea (OSA) is common among bariatric surgery patients and is associated with perioperative risk. Preoperative screening is recommended, but some screening tools lack validation, and their relative performance is unclear in this population. The study objective was to compare the ability of four existing tools (STOP-BANG, NO-OSAS, No-Apnea, and the Epworth Sleepiness Scale [ESS]) to screen for moderate to severe OSA in a diverse bariatric cohort. METHODS: Data from patients presenting for first-time bariatric surgery who underwent a sleep study within 1 year of the initial encounter were retrospectively reviewed. Performance of the four tools for detecting moderate to severe OSA was compared based on the area under the receiver operating characteristic curves (AUC). RESULTS: Of the included 214 patients (83.2% female, median age 39 years), 45.3% had moderate to severe OSA. Based on AUC, STOP-BANG (0.75 [95% CI: 0.68-0.81], N = 185), NO-OSAS (0.76 [95% CI: 0.69-0.82], N = 185), and No-Apnea (0.69 [95% CI: 0.62-0.76], N = 190) had similar performance (P > 0.16). Compared with STOP-BANG and NO-OSAS, ESS (0.61 [95% CI: 0.54-0.68], N = 198) had a significantly lower AUC (P < 0.01). Hispanic/Latino self-identification, sex, or obesity class did not significantly modify test performance. CONCLUSIONS: STOP-BANG and NO-OSAS may be preferable to No-Apnea and ESS when screening bariatric surgery patients for moderate to severe OSA. Efforts to screen bariatric patients for OSA are recommended.

Acetazolamide for OSA and Central Sleep Apnea: A Comprehensive Systematic Review and Meta-Analysis.

BACKGROUND: Therapy options for OSA and central sleep apnea (CSA) are limited, thus many patients remain untreated. Clinically, acetazolamide is sometimes used for CSA; however, given overlapping pathophysiologic properties of OSA and CSA, we hypothesized that acetazolamide is equally effective for both types. Prior reviews focused on specific subtypes of sleep apnea, study designs, and languages, thus including few studies (typically ≤3) limiting insights. RESEARCH QUESTION: How efficacious is acetazolamide for sleep apnea, and is its effect modified by sleep apnea type or acetazolamide dose? STUDY DESIGN AND METHODS: We queried MEDLINE, EMBASE, and ClinicalTrials.gov from inception until March 11, 2019. Any study in which adults with OSA/CSA received oral acetazolamide vs no acetazolamide (control) that reported sleep apnea-related outcomes was eligible, independent of study design or language. Two reviewers independently assessed eligibility and abstracted data. Primary outcomes were apnea-hypopnea index (AHI) and oxygen saturation nadir. Quality of evidence (QoE) was rated with the use of Grades of Recommendation Assessment, Development and Evaluation methods. RESULTS: We included 28 studies (13 OSA/15 CSA; NSubjects,Acetazolamide = 542; NSubjects,Control = 553) that enabled meta-analyses for 24 outcomes. Acetazolamide doses ranged from 36 to 1000 mg/d and treatment duration from 1 to 90 d (median, 6 d). Overall, acetazolamide vs control lowered the AHI by -0.7 effect sizes (95% CI, -0.83 to -0.58; I2 = 0%; moderate QoE) that corresponded to a reduction of 37.7% (95% CI, -44.7 to -31.3) or 13.8/h (95% CI, -16.3 to -11.4; AHIControl = 36.5/h). The AHI reduction was similar in OSA vs CSA, but significantly greater with higher doses (at least up to 500 mg/d). Furthermore, acetazolamide improved oxygen saturation nadir by +4.4% (95% CI, 2.3 to 6.5; I2 = 63%; no evidence of effect modification; very low QoE) and several secondary outcomes that included sleep quality measures and BP (mostly low QoE). INTERPRETATION: Short-term acetazolamide improved both OSA and CSA. Rigorous studies with long-term follow up are warranted to assess Acetazolamide's value for the chronic treatment of patients with sleep apnea. CLINICAL TRIAL REGISTRATION: PROSPERO (CRD42019147504).

Effect of Venlafaxine on Apnea-Hypopnea Index in Patients With Sleep Apnea: A Randomized, Double-Blind Crossover Study.

BACKGROUND: One of the key mechanisms underlying OSA is reduced pharyngeal muscle tone during sleep. Data suggest that pharmacologic augmentation of central serotonergic/adrenergic tone increases pharyngeal muscle tone. RESEARCH QUESTION: We hypothesized that venlafaxine, a serotonin-norepinephrine reuptake inhibitor, would improve OSA severity. STUDY DESIGN AND METHODS: In this mechanistic, randomized, double-blind, placebo-controlled crossover trial, 20 patients with OSA underwent two overnight polysomnograms ≥ 4 days apart, receiving either 50 mg of immediate-release venlafaxine or placebo before bedtime. Primary outcomes were the apnea-hypopnea index (AHI) and peripheral oxygen saturation (Spo2) nadir, and secondary outcomes included sleep parameters and pathophysiologic traits with a view toward understanding the impact of venlafaxine on mechanisms underlying OSA. RESULTS: Overall, there was no significant difference between venlafaxine and placebo regarding AHI (mean reduction, -5.6 events/h [95% CI, -12.0 to 0.9]; P = .09) or Spo2 nadir (median increase, +1.0% [-0.5 to 5]; P = .11). Venlafaxine reduced total sleep time, sleep efficiency, and rapid eye movement (REM) sleep, while increasing non-REM stage 1 sleep (Pall < .05). On the basis of exploratory post hoc analyses venlafaxine decreased ("improved") the ventilatory response to arousal (-30%; P = .049) and lowered ("worsened") the predicted arousal threshold (-13%; [P = .02]; ie, more arousable), with no effects on other pathophysiologic traits (Pall ≥ .3). Post hoc analyses further suggested effect modification by arousal threshold (P = .002): AHI improved by 19% in patients with a high arousal threshold (-10.9 events/h [-3.9 to -17.9]) but tended to increase in patients with a low arousal threshold (+7 events/h [-2.0 to 16]). Other predictors of response were elevated AHI and less collapsible upper airway anatomy at baseline (|r| > 0.5, P ≤ .02). INTERPRETATION: In unselected patients, venlafaxine simultaneously worsened and improved various pathophysiologic traits, resulting in a zero net effect. Careful patient selection based on pathophysiologic traits, or combination therapy with drugs countering its alerting effects, may produce a more robust response. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02714400; URL: www.clinicaltrials.gov.

Side effects of acetazolamide: a systematic review and meta-analysis assessing overall risk and dose dependence.

INTRODUCTION: Acetazolamide (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. METHODS: We 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. RESULTS: We 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). DISCUSSION: This 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.