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.

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.

Optimizing B-lines on lung ultrasound: an in-vitro to in-vivo pilot study with clinical implications.

B-lines on lung ultrasound (US) are the hallmark of pulmonary edema. It is unknown if ultrasound machine settings or probe type matter. We created an in-vitro gelatin model. Using lung presets as baseline, five blinded investigators assessed the impact of 32 distinct settings on B-line visibility based on a Likert-Scale (LS) from 0 to10 (< 5 worse, > 5 better) separately for two probes. The experiment was then repeated in-vivo in a patient with known pulmonary edema. Based on a multivariable regression LS-ratings were similar when comparing the in-vitro versus in-vivo experiment (P = 0.16; partial R2 = 0.2%) and when using the curvilinear versus linear probe (P = 0.69; partial R2 = 0.02%) but significantly different across machine settings (P < 0.0001; partial R2 = 34.4%). Limited by its pilot character, our study suggests that (1) certain US-machine settings heavily impact B-line visibility, with no clear difference between probes; (2) in-vitro models are a valid and practical alternative to more challenging patient-based research; (3) there is significant potential to improve B-line visibility and thus diagnostic yield in the clinical setting by using lung presets, centering the focal zone at the pleural line and increasing the distal time gain compensation, most of which are (in our experience) rarely done.

Checklist for Early Recognition and Treatment of Acute Illness (CERTAIN): evolution of a content management system for point-of-care clinical decision support.

BACKGROUND: The Checklist for Early Recognition and Treatment of Acute Illness (CERTAIN) is an international collaborative project with the overall objective of standardizing the approach to the evaluation and treatment of critically ill patients world-wide, in accordance with best-practice principles. One of CERTAIN's key features is clinical decision support providing point-of-care information about common acute illness syndromes, procedures, and medications in an index card format. METHODS: This paper describes 1) the process of developing and validating the content for point-of-care decision support, and 2) the content management system that facilitates frequent peer-review and allows rapid updates of content across different platforms (CERTAIN software, mobile apps, pdf-booklet) and different languages. RESULTS: Content was created based on survey results of acute care providers and validated using an open peer-review process. Over a 3 year period, CERTAIN content expanded to include 67 syndrome cards, 30 procedure cards, and 117 medication cards. 127 (59 %) cards have been peer-reviewed so far. Initially MS Word® and Dropbox® were used to create, store, and share content for peer-review. Recently Google Docs® was used to make the peer-review process more efficient. However, neither of these approaches met our security requirements nor has the capacity to instantly update the different CERTAIN platforms. CONCLUSION: Although we were able to successfully develop and validate a large inventory of clinical decision support cards in a short period of time, commercially available software solutions for content management are suboptimal. Novel custom solutions are necessary for efficient global point of care content system management.

Development and validation of clinical performance assessment in simulated medical emergencies: an observational study.

BACKGROUND: Critical illness is a time-sensitive process which requires practitioners to process vast quantities of data and make decisions rapidly. We have developed a tool, the Checklist for Early Recognition and Treatment of Acute Illness (CERTAIN), aimed at enhancing care delivery in such situations. To determine the efficacy of CERTAIN and similar cognitive aids, we developed rubric for evaluating provider performance in a simulated medical resuscitation environments. METHODS: We recruited 18 clinicians with current valid ACLS certification for evaluation in three simulated medical scenarios designed to mimic typical medical decompensation events routinely experienced in clinical care. Subjects were stratified as experienced or novice based on prior critical care training. A checklist of critical actions was designed using face validity for each scenario to evaluate task completion and performance. Simulation sessions were video recorded and scored by two independent raters. Construct validity was assessed under the assumption that experienced clinicians should perform better than novice clinicians on each task. Reliability was assessed as percentage agreement, kappa statistics and Bland-Altman plots as appropriate. RESULTS: Eleven experts and seven novices completed evaluation. The overall agreement on common checklist item completion was 84.8 %. The overall model achieved face validity and was consistent with our construct, with experienced clinicians trending towards better performance compared to novices for accuracy and speed of task completion. CONCLUSIONS: A standardized video assessment tool has potential to provide a valid and reliable method to assess 12 performances of clinicians facing simulated medical emergencies.

Male-predominant plasma transfusion strategy for preventing transfusion-related acute lung injury: a systematic review.

OBJECTIVES: To assess 1) the effectiveness of male-predominant plasma transfusion strategy for preventing transfusion-related acute lung injury and related mortality; and 2) whether this effect varies across different patient subgroups. DESIGN: Systematic Review and meta-analysis: Data were identified by querying MEDLINE and EMBASE (including proceedings of major conferences on blood transfusions), searching the Internet for hemovigilance reports, reviewing reference lists of eligible articles and contacting experts in the field. Eligible were all studies reporting transfusion-related acute lung injury incidence, all-cause mortality (primary outcomes), hospital length of stay, time to extubation, PaO2/FIO2-ratio or blood pressure changes (secondary outcomes) in recipients of plasma transfusions containing relatively more plasma from individuals at low risk of carrying leukocyte-antibodies ("male plasma") than those receiving comparator plasma ("control plasma"). No limits were placed on study design, population or language. The only exclusion criteria were non-human subjects and lack of control group. Prespecified study quality indicators (including risk of bias assessment) and potential effect modifiers were tested using Cochran's Q Test. Final analyses using random-effects models and I2 to assess heterogeneity were performed in the subset of studies judged to provide the best evidence and separately for significantly different subgroups using STATA 12.1 (StataCorp, College Station, TX). SETTING: As per primary studies. PATIENTS/SUBJECTS: As per primary studies. INTERVENTIONS: As per primary studies (generally: exposure to plasma containing relatively more male plasma than comparator plasma). MEASUREMENTS AND MAIN RESULTS: From a total of 850 retrieved records, we identified 45 eligible studies. For transfusion-related acute lung injury incidence, final analysis was restricted to 13 cohort studies and one randomized controlled trial in which transfusion-related acute lung injury cases only involved plasma transfusions. Risk of transfusion-related acute lung injury and mortality in plasma recipients exposed to men when compared with control plasma were 0.27 (95% CI, 0.20-0.38; p < 0.001; I = 0%; n = 14; 286 events) and 0.89 (95% CI, 0.80-1.00; p = 0.04; I = 79%; n = 7; 5, 710 events), respectively. No other significant interactions were found. Secondary outcomes showed similar results but were less reported and the studies were more heterogeneous. Sensitivity analyses did not alter the results. There was no evidence of publication bias. DISCUSSION: More than 800 million people in 17 countries are subject to male-predominant plasma transfusion policy and at least three more countries are planning or considering adoption of this strategy. On the basis of most observational data, judged to be of high quality, male-predominant plasma transfusion strategy reduces plasma-related transfusion-related acute lung injury incidence and possibly mortality. There was no evidence that the effect differs across patient subgroups, but power to detect such differences was low.

Decision support tool for differential diagnosis of Acute Respiratory Distress Syndrome (ARDS) vs Cardiogenic Pulmonary Edema (CPE): a prospective validation and meta-analysis.

INTRODUCTION: We recently presented a prediction score providing decision support with the often-challenging early differential diagnosis of acute lung injury (ALI) vs cardiogenic pulmonary edema (CPE). To facilitate clinical adoption, our objective was to prospectively validate its performance in an independent cohort. METHODS: Over 9 months, adult patients consecutively admitted to any intensive care unit of a tertiary-care center developing acute pulmonary edema were identified in real-time using validated electronic surveillance. For eligible patients, predictors were abstracted from medical records within 48 hours of the alert. Post-hoc expert review blinded to the prediction score established gold standard diagnosis. RESULTS: Of 1,516 patients identified by electronic surveillance, data were abstracted for 249 patients (93% within 48 hours of disease onset), of which expert review (kappa 0.93) classified 72 as ALI, 73 as CPE and excluded 104 as "other". With an area under the curve (AUC) of 0.81 (95% confidence interval = 0.73 to 0.88) the prediction score showed similar discrimination as in prior cohorts (development AUC = 0.81, P = 0.91; retrospective validation AUC = 0.80, P = 0.92). Hosmer-Lemeshow test was significant (P = 0.01), but across eight previously defined score ranges probabilities of ALI vs CPE were the same as in the development cohort (P = 0.60). Results were the same when comparing acute respiratory distress syndrome (ARDS, Berlin definition) vs CPE. CONCLUSION: The clinical prediction score reliably differentiates ARDS/ALI vs CPE. Pooled results provide precise estimates of the score's performance which can be used to screen patient populations or to assess the probability of ALI/ARDS vs CPE in specific patients. The score may thus facilitate early inclusion into research studies and expedite prompt treatment.

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.

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).

Effect of obesity on sleep apnea pathogenesis differs in women versus men: multiple mediation analyses in the retrospective SNOOzzzE cohort.

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 has not been fully described. Thus we sought to evaluate how obesity leads to OSA and assess how these mechanisms differ between men and women. The San Diego Multi-Outcome OSA Endophenotype (SNOOzzzE) cohort includes 3,319 consecutive adults who underwent a clinical in-laboratory polysomnography at the University of California, San Diego, sleep clinic between January 2017 and December 2019. Using routine polysomnography signals, we determined OSA endotypes. We then performed mediation analyses stratified by sex to determine how BMI influenced the apnea-hypopnea index (AHI) using OSA pathophysiological traits as mediators, adjusting for age, race, and ethnicity. We included 2,146 patients of whom 919 (43%) were women and 1,227 (57%) were obese [body mass index (BMI) > 30 kg/m2]. BMI was significantly associated with AHI in both women and men. In men, the adjusted effect of BMI on AHI was partially mediated by a reduction in upper airway stiffness (ßstandardized = 0.124), a reduction in circulatory delay (ßstandardized = 0.063), and an increase in arousal threshold (ßstandardized = 0.029; Pboot-strapped,all < 0.05). In women, the adjusted effect of BMI on AHI was partially mediated by a reduction in upper airway stiffness (ßstandardized = 0.05) and circulatory delay (ßstandardized = 0.037; Pboot-strapped,all < 0.05). BMI-related OSA pathogenesis differs by sex. An increase in upper airway collapsibility is consistent with prior studies. A reduction in circulatory delay may lead to shorter and thus more events per hour (higher AHI), while the relationship between arousal threshold and OSA is likely complex.NEW & NOTEWORTHY Our data provide important insights into obesity-related obstructive sleep apnea (OSA) pathogenesis, thereby validating, and extending, prior research findings. This is the largest sample size study to examine the relationships between obesity and gender on OSA pathogenesis. The influence of obesity on sleep apnea severity is mediated by different mechanistic traits (endotypes).

Treatment of Sleep Apnea and Reduction in Blood Pressure: The Role of Heart Rate Response and Hypoxic Burden.

BACKGROUND: Obstructive sleep apnea is associated with increased blood pressure (BP). Obstructive sleep apnea treatment reduces BP with substantial variability, not explained by the apnea-hypopnea index, partly due to inadequate characterization of obstructive sleep apnea's physiological consequences, such as oxygen desaturation, cardiac autonomic response, and suboptimal treatment efficacy. We sought to examine whether a high baseline heart rate response (ΔHR), a marker of high cardiovascular risk in obstructive sleep apnea, predicts a larger reduction in post-treatment systolic BP (SBP). Furthermore, we aimed to assess the extent to which a reduction in SBP is explained by a treatment-related reduction in hypoxic burden (HB). METHODS: ΔHR and HB were measured from pretreatment and posttreatment polygraphy, followed by a 24-hour BP assessment in 168 participants treated with continuous positive airway pressure or nocturnal supplemental oxygen from the HeartBEAT study (Heart Biomarker Evaluation in Apnea Treatment). Multiple linear regression models assessed whether high versus mid (reference) ΔHR predicted a larger reduction in SBP (primary outcome) and whether there was an association between treatment-related reductions in SBP and HB. RESULTS: A high versus mid ΔHR predicted improvement in SBP (adjusted estimate, 5.8 [95% CI, 1.0-10.5] mm Hg). Independently, a greater treatment-related reduction in HB was significantly associated with larger reductions in SBP (4.2 [95% CI, 0.9-7.5] mm Hg per 2 SD treatment-related reduction in HB). Participants with substantial versus minimal treatment-related reductions in HB had a 6.5 (95% CI, 2.5-10.4) mm Hg drop in SBP. CONCLUSIONS: A high ΔHR predicted a more favorable BP response to therapy. Furthermore, the magnitude of the reduction in BP was partly explained by a greater reduction in HB.

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.

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.

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.

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.

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.

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.