Hypoxic Burden Research Articles

Effect of norepinephrine reuptake inhibitors combined with antimuscarinic agents vs monotherapy for OSA: a systematic review and meta-analysis.

Randomized controlled trials have shown that combining norepinephrine reuptake inhibitors and antimuscarinics can ameliorate the severity of obstructive sleep apnea. This article explores whether the effectiveness and safety of combining norepinephrine reuptake inhibitors with antimuscarinic agents surpass monotherapy for treating obstructive sleep apnea. We searched randomized controlled trials including adult patients with obstructive sleep apnea who received combination therapy and monotherapy in 8 databases from inception until April 5, 2023 and evaluated the studies' quality and conducted a meta-analysis and systematic review. The primary outcome was the apnea-hypopnea index. Secondary outcome measures included loop gain, hypoxic burden, oxygen desaturation index, and ventilation at low ventilatory drive, among other indicators. We assessed the quality of the studies using Cochrane Methods criteria. We identified 4 randomized controlled trials for systematic review and 2 for meta-analysis. The results of the meta-analysis showed that norepinephrine reuptake inhibitors combined with antimuscarinic agents in patients with obstructive sleep apnea prolonged total sleep time by a mean of 28.20 minutes [95% confidence interval (5.78, 50.61), P = .01] and increased sleep efficiency by 4.73% [95% confidence interval (0.50, 8.97), P = .03] compared with norepinephrine reuptake inhibitors alone. Other indices and adverse events were of no statistical significance. The systematic reviews revealed that norepinephrine reuptake inhibitors combined with antimuscarinics may be superior to monotherapy in improving apnea-hypopnea index and endotypic traits. This evaluation demonstrated the potential advantages of combining norepinephrine reuptake inhibitors plus antimuscarinics for treating OSA compared with norepinephrine reuptake inhibitors alone and revealed no statistically significant difference in drug safety. Wang J, Ye Y, Shang Z, etal. Effect of norepinephrine reuptake inhibitors combined with antimuscarinic agents vs monotherapy for OSA: a systematic review and meta-analysis. J Clin Sleep Med. 2024;20(8):1363-1372.

Hypoxic burden: searching for new methods to measure the severity and impact of obstructive sleep apnea

Hypoxic burden: searching for new methods to measure the severity and impact of obstructive sleep apnea

Association between sleep apnea-specific hypoxic burden and severity of coronary artery disease

PurposeSleep apnea-specific hypoxic burden (SASHB) is a polysomnographic metric that comprehensively measures the degree of nocturnal desaturation caused by obstructive sleep apnea. This research was conducted to elucidate the relationship between SASHB and coronary artery disease (CAD) severity.MethodsWe carried out a prospective study of hospitalized patients with CAD of unstable angina who were expected to undergo invasive coronary angiography at Beijing Anzhen Hospital from February to September 2023. SASHB values were calculated using a self-programmed C + + program. Multivariable logistic regression analysis was applied to identify the association between SASHB and the prevalence of severe CAD, documented by the Gensini Score, and the SYNTAX (Synergy between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) Score.ResultsThis study enrolled 137 patients with a median age of 59 years, 96 (70.1%) of whom were male. A total of 125 (91.2%) patients had coronary stenosis of ≥ 50% in at least one location. Patients with a high SASHB of ≥ 18% min/h had a significantly higher Gensini Score (32.0 vs. 18.5, P = 0.002) and SYNTAX Score (14.0 vs. 7.0, P = 0.002) than those with a low SASHB. After adjusting for multiple covariates, a high SASHB was significantly associated with the prevalence of severe CAD, determined by a Gensini Score ≥ 21 (OR 2.67, P = 0.008) or a SYNTAX Score > 22 (OR 4.03, P = 0.016).ConclusionOur findings revealed a robust and independent association between SASHB and CAD severity in patients with unstable angina, highlighting the potential value of SASHB as a predictor of risk and a target for interventions aimed at preventing cardiovascular diseases.Trial registrationChinese Clinical Trial Registry No. ChiCTR2300067991 on February 2, 2023.

Polysomnographic characteristics of excessive daytime sleepiness phenotypes in obstructive sleep apnea: Results from the international Sleep Apnea Global Interdisciplinary Consortium (SAGIC).

Excessive daytime sleepiness (EDS) is a major symptom of obstructive sleep apnea (OSA). Traditional polysomnographic (PSG) measures only partially explain EDS in OSA. This study analyzed traditional and novel PSG characteristics of two different measures of EDS among OSA patients. Sleepiness was assessed using the Epworth Sleepiness Scale (>10 points defined as "risk of dozing") and a measure of general sleepiness (feeling sleepy ≥3 times/week defined as "feeling sleepy"). Four sleepiness phenotypes were identified: "non-sleepy", "risk of dozing only", "feeling sleepy only" and "both at risk of dozing and feeling sleepy". Altogether, 2083 OSA patients (69% male) with an apnea-hypopnea index (AHI) ≥5 events/hour were studied; 46% were "non-sleepy", 26% at "risk of dozing only", 7% were "feeling sleepy only" and 21% reported both. The two phenotypes at "risk of dozing" had higher AHI, more severe hypoxemia (as measured by oxygen desaturation index, minimum and average oxygen saturation [SpO2], time spent <90% SpO2, and hypoxic burden) and they spent less time awake, had shorter sleep latency, and higher heart rate response to arousals than "non-sleepy" and "feeling sleepy only" phenotypes. While statistically significant, effect sizes were small. Sleep stages, frequency of arousals, wake after sleep onset and limb movement did not differ between sleepiness phenotypes after adjusting for confounders. In a large international group of OSA patients, PSG characteristics were weakly associated with EDS. The physiological measures differed among individuals characterized as "risk of dozing" or "non-sleepy", while "feeling sleepy only" did not differ from "non-sleepy" individuals.

On the relationship between Hypoxic Burden and standard PSG variables for obstructive sleep apnea diagnosis and prediction

On the relationship between Hypoxic Burden and standard PSG variables for obstructive sleep apnea diagnosis and prediction

Effect of positional therapy on the sleep apnea-specific hypoxic burden and pulse rate response in children with positional Obstructive Sleep Apnea

Effect of positional therapy on the sleep apnea-specific hypoxic burden and pulse rate response in children with positional Obstructive Sleep Apnea

Effect of high flow nasal cannula and continuous positive airway pressure on the sleep apnea-specific hypoxic burden and pulse rate response in children with Obstructive Sleep Apnea

Effect of high flow nasal cannula and continuous positive airway pressure on the sleep apnea-specific hypoxic burden and pulse rate response in children with Obstructive Sleep Apnea

Association between Sleep Apnoea-Specific Hypoxic Burden and blood pressure in children with OSA

Association between Sleep Apnoea-Specific Hypoxic Burden and blood pressure in children with OSA

Improvement in sleep apnea-specific hypoxic burden with novel oral appliance O2Vent Optima and oral positive pressure accessory ExVent

Improvement in sleep apnea-specific hypoxic burden with novel oral appliance O2Vent Optima and oral positive pressure accessory ExVent

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

RationaleAcetazolamide 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...

All Obstructive Sleep Apnea Events Are Not Created Equal: The Relationship between Event-related Hypoxemia and Physiologic Response.

Rationale: Obstructive sleep apnea (OSA) severity is typically assessed by the apnea-hypopnea index (AHI), a frequency-based metric that allocates equal weight to all respiratory events. However, more severe events may have a greater physiologic impact. Objectives: The purpose of this study was to determine whether the degree of event-related hypoxemia would be associated with the postevent physiologic response. Methods: Patients with OSA (AHI, ⩾5/h) from the multicenter Canadian Sleep and Circadian Network cohort were studied. Using mixed-effect linear regression, we examined associations between event-related hypoxic burden (HBev) assessed by the area under the event-related oxygen saturation recording with heart rate changes (ΔHRev), vasoconstriction (vasoconstriction burden [VCBev] assessed with photoplethysmography), and electroencephalographic responses (power ratio before and after events). Results: Polysomnographic recordings from 658 patients (median [interquartile range] age, 55.00 [45.00, 64.00] yr; AHI, 27.15 [14.90, 64.05] events/h; 42% female) were included in the analyses. HBev was associated with an increase in all physiologic responses after controlling for age, sex, body mass index, sleep stage, total sleep time, and study centers; for example, 1 standard deviation increase in HBev was associated with 0.21 [95% confidence interval, 0.2, 0.22], 0.08 [0.08, 0.09], and 0.22 [0.21, 0.23] standard deviation increases in ΔHRev, VCBev, and β-power ratio, respectively. Conclusions: Increased event-related hypoxic burden was associated with greater responses across a broad range of physiologic signals. Future metrics that incorporate information about the variability of these physiologic responses may have promise in providing a more nuanced assessment of OSA severity.

Associations between Nocturnal Hypoxemia and Retinal Nerve Fiber Layer Thinning: The Nagahama Study.

Rationale: There have been meta-analyses that showed reduced retinal nerve fiber layer (RNFL) thickness, which is a surrogate marker of glaucoma, in patients with obstructive sleep apnea (OSA). However, the sample sizes in these reports were small (<300), and the mechanism of RNFL thinning in patients with OSA was not revealed.Objectives: To investigate the relationship of RNFL thickness with nocturnal hypoxemia or hypoxemic burden in a large-scale study.Methods: In this epidemiological study, 8,309 community residents were enrolled. The actigraphy-modified 3% oxygen desaturation index (acti-ODI3%) and cumulative percentage of sleep time with oxygen saturation <90% (acti-CT90) modified by objective sleep duration using actigraphy were measured. The hypoxemic burden is shown as acti-CT90. Circumpapillary RNFL thickness was determined using optical coherence tomography.Results: Multivariable logistic analysis models revealed that an increase in acti-CT90 was significantly associated with mean RNFL thinning after adjusting for several factors in participants without glaucoma diagnosed or treated previously (β = -0.037; P = 0.009). There were significant differences in mean RNFL thickness among participants stratified according to acti-CT90 (>1.5 vs. ⩽1.5; P = 0.04). Although acti-ODI3% was significantly associated with acti-CT90 (β = 0.72; P < 0.0001), acti-ODI3% was not significantly associated with mean RNFL thickness in the multivariable logistic analysis (β = -0.011; P = 0.48). In addition, acti-CT90 was significantly associated with mean RNFL thickness both in the elderly (⩾60 yr; β = -0.058; P = 0.002) and nonelderly (<60 yr; β = -0.054; P = 0.007).Conclusions: Acti-CT90, but not acti-ODI3%, was associated with mean RNFL thinning in participants irrespective of age in the elderly or nonelderly. Further prospective studies are required to investigate whether the prevention of hypoxic burden, which was shown as acti-CT90 in this study, is favorable for RNFL thinning.

REducing Sleep Apnoea for the PrEvention of Dementia (REShAPED): Protocol for a multi-site feasibility randomised controlled trial

There is accumulating evidence that has linked OSA with increased risk of cognitive decline and dementia. Here we present the protocol for an Australian, multi-site randomised controlled, parallel open-label trial which will evaluate the feasibility for a full-scale trial investigating the effects of treating OSA on cognitive decline in older adults at risk of dementia within memory clinic settings. We will randomise 180 older adults to either the treatment intervention group or control group for 2 years. Inclusion criteria include: 50–85 years; mild-severe OSA (defined average ODI ≥ 10 with 3% oxygen desaturation determined by wrist oximetry over two nights); and subjective cognitive complaints or mild cognitive impairment. The treatment intervention arm aims to achieve an optimal treatment response based on reducing hypoxic burden with either CPAP, mandibular advancement splint, positional therapy, or oxygen therapy. Furthermore, participants will receive up to 8 sessions which involve motivational interviewing, collaborative goal setting, and behavioural sleep management. The control arm will not receive OSA treatment as part of this trial, however there will be no OSA treatment restrictions, and any treatment will be documented. Primary outcomes are 1) acceptability based upon willingness of participants to be randomised; 2) alleviating hypoxic burden by reducing OSA severity; 3) tolerability of the trial burden based upon collection of outcomes over the 2-year follow-up. Secondary outcomes include safety and cognitive function. Outcomes will be collected at 0, 6 and 24-months. This feasibility study aims to will provide the basis for a larger longer-term trial of dementia prevention.

Association between normalized lactate load and in-hospital mortality in patients with acute myocardial infarction

BackgroundLactate was a prognostic indicator for acute myocardial infarction (AMI) patients. However, the association between normalized lactate load, representing hypoxic burden over time, and in-hospital mortality remained uncertain. MethodsThe data for this study was obtained from the Medical Information Mart for Intensive Care IV (MIMIC-IV, version 2.1) database. The normalized lactate load, describing the average intensity of hyperlactatemia, was calculated as the area under the curve (AUC) of lactate divided by time. 5882 AMI patients enrolled in this study were divided into survivor (n = 5015), and non-survivor group (n = 867). The primary endpoint was in-hospital mortality. Receiver operating characteristic (ROC) curves were generated to assess the predictive efficacy of normalized lactate load for in-hospital mortality, and areas under the curves of different parameters were compared using DeLong test. Multivariate binary logistic regression analysis was employed to explore the association between normalized lactate load and in-hospital mortality. The adjusting variables included age, gender, ethnicity, heart rate, systolic blood pressure, congestive heart failure, shock, dyslipidemia, cardiac arrest, cerebrovascular disease, neutrophil, lymphocyte, creatinine, blood nitrogen urea, clopidogrel, beta-blockers, angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB), statins, dialysis, extracorporeal membrane oxygenation (ECMO), the Sequential Organ Failure Assessment (SOFA) score and Simplified Acute Physiology Score II (SAPS II). Restricted cubic spline (RCS) was conducted to evaluate nonlinear associations of normalized lactate load with in-hospital mortality. ResultsThe overall in-hospital mortality rate was 14.7%. After adjusting for confounding variables, normalized lactate load was independently associated with increased risk of in-hospital mortality (Normalized lactate load≥2.6 vs Normalized lactate load<2.6: OR, 95% CI: 1.56, 1.27–1.93). The RCS demonstrated a positive linear relationship between normalized lactate load and in-hospital mortality (non-linear p = 0.725). ROC curves showed that normalized lactate load was better than first lactate, maximum lactate, and mean lactate in predicting in-hospital mortality, but lower than SOFA and SAPS II. Among participants with at least nine lactate measures, normalized lactate load showed predictive performance comparable to SOFA and SAPS II. ConclusionNormalized lactate load can be used to predict the prognosis of in-hospital mortality in AMI patients, and its prediction performance increases with the increase of lactate measurement.

Association between intermittent hypoxemia and neurodevelopmental outcomes in extremely premature infants: A single-center experience

ObjectiveTo describe the association between intermittent hypoxemic events (IHEs) and severe neurodevelopmental impairment (SNDI) or death in extremely premature infants. Study designRetrospective study of extremely premature infants 230/7–276/7 weeks gestational age (GA) and birthweight (BW) ≤1250 g (g) admitted to a level IV neonatal intensive care unit (NICU) from 2013 to 2017. IHEs, defined as events with SpO2 ≤ 80 % lasting 10 s to 5 min, were algorithmically identified using data extracted from bedside monitors at 2 s intervals (0.5 Hz). The primary outcome was SNDI at 18–24 months corrected age (CA), defined as a Bayley-III motor, language or cognitive composite score ≤69, or death before discharge while the secondary outcome was SNDI alone. We used mixed-effects regression models to evaluate the relationship between mean daily IHE rate per postnatal week of life for the first 12 weeks and the outcomes, and logistic regression models to assess the association between outcomes and summary measures of hypoxic burden for the entire NICU hospitalization. ResultsThe mortality rate was 7 % (18/249) during NICU hospitalization. Of 249 infants born during this time period, IHE and neurodevelopmental outcome data were fully available for 65 infants (mean GA 26 ± 1.4 weeks, mean birth weight (BW) 738 ± 199 g). The outcome of SNDI alone occurred in 34 % (22/65) with a majority demonstrating motor or language delay on the Bayley-III. Although mean daily IHE rate/week was not associated with SNDI or death, total IHE duration was associated with increased odds of SNDI (OR (95 % CI) 1.03 (1.01, 1.05), p = 0.008) in models adjusted for GA. ConclusionsIn a cohort of extremely premature infants 23–27 weeks GA, each hour of total IHE duration (SpO2 ≤ 80 %) was associated with a 2.7 % (0.7 %, 4.8 %) increase in the odds of SNDI at 18–24 months CA.

O008 Refining the Hypoxic Burden Algorithm by Investigating different Methods for Calculating the SpO2 Baseline

Abstract Introduction Intermittent hypoxia is a key mechanism linking Obstructive Sleep Apnoea (OSA) to cardiovascular disease (CVD). Oximetry analysis could enhance understanding of which OSA phenotypes are associated with CVD risk. The hypoxic burden (HB) is a measure calculated from the oximetry signal that shows promise for predicting CVD mortality, but its calculation is complex. With a view to simplifying its calculation, we investigated three different baseline calculation methods and its impact on predicting CVD mortality for the HB algorithm. Methods Data from Sleep Heart Health Study (SHHS) with CVD mortality outcome and complete covariate information was used. We implemented the HB method of Azarbarzin et al 2018 ERJ. The three baseline methods included an event-based baseline (same as Azarbarzin et al 2018 ERJ), a record-based baseline, and a fixed baseline. The performance of each parameter in predicting CVD mortality was assessed using an adjusted Cox proportional hazard ratio (HR) analysis. Results The best performing method was the record-based baseline method which returned a fully adjusted model hazard ratio of 1.83 (95% CI: 1.03-3.27, p&amp;lt;0.05). The results for the event-based and record-based baseline methods were 1.60 (95% CI: 0.86-3.00, p=0.14) and 1.73 (95% CI: 0.93-3.22, p=0.08) respectively. Discussion HB with the record-based baseline was easier to calculate than the original event-based baseline method by Azarbarzin at al. and resulted in improved CVD mortality prediction performance. We believe that this method provides a step towards providing a novel parameter with easy calculation providing early risk stratification in cardiovascular patients.

Associations of baseline obstructive sleep apnea and sleep macroarchitecture with cognitive function after 8 years in middle-aged and older men from a community-based cohort study.

Previous prospective studies examining associations of obstructive sleep apnea and sleep macroarchitecture with future cognitive function recruited older participants, many demonstrating baseline cognitive impairment. This study examined obstructive sleep apnea and sleep macroarchitecture predictors of visual attention, processing speed, and executive function after 8 years among younger community-dwelling men. Florey Adelaide Male Ageing Study participants (n = 477) underwent home-based polysomnography, with 157 completing Trail-Making Tests A and B and the Mini-Mental State Examination. Associations of obstructive sleep apnea (apnea-hypopnea index, oxygen desaturation index, and hypoxic burden index) and sleep macroarchitecture (sleep stage percentages and total sleep time) parameters with future cognitive function were examined using regression models adjusted for baseline demographic, biomedical, and behavioural factors, and cognitive task performance. The mean (standard deviation) age of the men at baseline was 58.9 (8.9) years, with severe obstructive sleep apnea (apnea-hypopnea index ≥30 events/h) in 9.6%. The median (interquartile range) follow-up was 8.3 (7.9-8.6) years. A minority of men (14.6%) were cognitively impaired at baseline (Mini-Mental State Examination score <28/30). A higher percentage of light sleep was associated with better Trail-Making Test A performance (B = -0.04, 95% confidence interval [CI] -0.06, -0.01; p = 0.003), whereas higher mean oxygen saturation was associated with worse performance (B = 0.11, 95% CI 0.02, 0.19; p = 0.012). While obstructive sleep apnea and sleep macroarchitecture might predict cognitive decline, future studies should consider arousal events and non-routine hypoxaemia measures, which may show associations with cognitive decline.

Association of hypoxic burden metrics with cardiovascular outcomes in heart failure and sleep-disordered breathing.

Heart failure (HF) and sleep-disordered breathing (SDB) frequently coexist. We aimed to compare the prognostic value of different nocturnal hypoxic burden metrics in hospitalized HF patients. HF patients underwent polygraphy screening for SDB in this prospective cohort. Hypoxic burden metrics assessed using pulse oximetry included time<90% oxygen saturation (T90), proportion of total recording time<90% oxygen saturation (TRT90), oxygen desaturation index (ODI), and mean oxygen saturation (meanSO2 ). The prespecified endpoints were the composite of cardiovascular death or admission for worsening HF. This study included 764 hospitalized HF patients, 16.5% and 36.6% of whom had obstructive and central sleep apnoea, respectively. With a median follow-up time of 2.2years, endpoint events occurred in 410 (53.7%) patients. In univariate and multivariate analyses, T90, TRT90, and meanSO2 were substantially associated with the composite outcome, whereas ODI was not. After multivariate Cox model adjustment, patients with 5.0≤T90≤52.0min [hazard ratio (HR) 1.32, 95% confidence interval (CI): 1.02-1.71, P=0.034] or T90>52.0min (HR 1.56, 95% CI: 1.21-2.02, P=0.001) had a greater risk of the composite outcome than those with T90<5.0min. The TRT90 and T90 results were similar. Compared with meanSO2 >95%, meanSO2 <93% (HR 1.47, 95% CI: 1.16-1.88, P=0.002) was correlated with adverse outcomes. The hypoxic burden metrics T90, TRT90, and meanSO2 , but not ODI, were independent predictors of cardiovascular death or readmission for worsening HF. Indicators of duration and severity, not just the frequency of nocturnal hypoxaemia, should be valued and considered for intervention to improve outcomes in HF patients.

Hypoxic sensitivity and burden predict propensity for respiratory plasticity in humans.

Hypoxic sensitivity and burden predict propensity for respiratory plasticity in humans.

Ventilatory Burden as a Measure of Obstructive Sleep Apnea Severity Is Predictive of Cardiovascular and All-Cause Mortality.

Rationale: The apnea-hypopnea index (AHI), used for the diagnosis of obstructive sleep apnea, captures only the frequency of respiratory events and has demonstrable limitations. Objectives: We propose a novel automated measure, termed "ventilatory burden" (VB), that represents the proportion of overnight breaths with less than 50% normalized amplitude, and we show its ability to overcome limitations of AHI. Methods: Data from two epidemiological cohorts (EPISONO [Sao Paolo Epidemiological Study] and SHHS [Sleep Heart Health Study]) and two retrospective clinical cohorts (DAYFUN; New York University Center for Brain Health) were used in this study to 1) derive the normative range of VB, 2) assess the relationship between degree of upper airway obstruction and VB, and 3) assess the relationship between VB and all-cause and cardiovascular disease (CVD) mortality with and without hypoxic burden that was derived using an in-house automated algorithm. Measurements and Main Results: The 95th percentiles of VB in asymptomatic healthy subjects across the EPISONO and the DAYFUN cohorts were 25.2% and 26.7%, respectively (median [interquartile range], VBEPISONO, 5.5 [3.5-9.7]%; VBDAYFUN, 9.8 [6.4-15.6]%). VB was associated with the degree of upper airway obstruction in a dose-response manner (VBuntreated, 31.6 [27.1]%; VBtreated, 7.2 [4.7]%; VBsuboptimally treated, 17.6 [18.7]%; VBoff-treatment, 41.6 [18.1]%) and exhibited low night-to-night variability (intraclass correlation coefficient [2,1], 0.89). VB was predictive of all-cause and CVD mortality in the SHHS cohort before and after adjusting for covariates including hypoxic burden. Although AHI was predictive of all-cause mortality, it was not associated with CVD mortality in the SHHS cohort. Conclusions: Automated VB can effectively assess obstructive sleep apnea severity, is predictive of all-cause and CVD mortality, and may be a viable alternative to the AHI.