Characterisation of Symptom and Polysomnographic Profiles Associated with Cardiovascular Risk in a Sleep Clinic Population with Obstructive Sleep Apnoea.

Aim: Recent data have identified specific symptom and polysomnographic profiles associated with cardiovascular disease (CVD) in patients with obstructive sleep apnoea (OSA). Our aim was to determine whether these profiles were present at diagnosis of OSA in patients with established CVD and in those with high cardiovascular risk. Participants in the Sydney Sleep Biobank (SSB) database, aged 30-74 years, self-reported presence of CVD (coronary artery disease, cerebrovascular disease, or heart failure). In those without established CVD, the Framingham Risk Score (FRS) estimated 10-year absolute CVD risk, categorised as "low" (<6%), "intermediate" (6-20%), or "high" (>20%). Groups were compared on symptom and polysomnographic variables. Results: 629 patients (68% male; mean age 54.3 years, SD 11.6; mean BMI 32.3 kg/m2, SD 8.2) were included. CVD was reported in 12.2%. A further 14.3% had a low risk FRS, 38.8% had an intermediate risk FRS, and 34.7% had a high risk FRS. Groups differed with respect to age, sex and BMI. OSA severity increased with established CVD and increasing FRS. The symptom of waking too early was more prevalent in the higher FRS groups (p=0.004). CVD and FRS groups differed on multiple polysomnographic variables; however, none of these differences remained significant after adjusting for age, sex, and BMI. Conclusion: Higher CVD risk was associated with waking too early in patients with OSA. Polysomnographic variations between groups were explained by demographic differences. Further work is required to explore the influence of OSA phenotypic characteristics on susceptibility to CVD.

A comparison of two obesity-related hypoventilation disorders: Impact on sleep, quality of life and neurocognitive outcomes and the effects of positive airway pressure therapy.

Study Objectives: Symptom impact and neurocognitive function have not been previously compared between patients with obesity-associated hypoventilation disorders (obesity hypoventilation syndrome [OHS]) and hypoventilation in the setting of obesity and obstructive airways disease (OHAD). The aim of this study is to compare baseline sleep-related symptoms, health-related quality of life, and neurocognitive function between OHS and OHAD and the impact of PAP therapy on these outcomes. Methods: Epworth Sleepiness Scale (ESS), Pittsburgh Sleepiness Quality Index (PSQI), SF36, and various neurocognitive tests, in addition to anthropometric, polysomnography, lung function, and blood gas data from participants with OHS and participants with OHAD, were included in the analysis. These data were originally collected in their respective randomized clinical trials, comparing the efficacy of different PAP modes (bilevel PAP vs. CPAP) in resolving hypercapnia. Between groups (OHS vs OHAD), pre- and post-treatment (with 3 months of positive airway pressure) comparisons were made using linear mixed modeling. Results: 45 OHS participants (mean age 51 years old, 33% female, BMI 52 kg/m2, FER 0.81, PaCO2 54 mmHg, AHI 87/h) and 32 OHAD participants (mean age 61years old, 31% female, BMI 43kg/m2, FER 0.60, PaCO2 54 mmHg, AHI 59/h) were included in the analysis. Both OHS and OHAD had similar baseline ESS (14(5.6) vs. 12(5.4)), Global PSQI (10(3.2) vs. 11(4.8)), SF36 and neurocognitive test performances (other than OHAD had lower digit symbol substitution test performance). Treatment with PAP therapy resulted in similar ESS, Global PSQI, and SF36 improvements in both groups. Neurocognitive performance did not significantly improve after PAP therapy in either group. Conclusions: The symptom impact between two separate hypoventilation disorders (OHS and OHAD), in terms of sleepiness, sleep quality, quality of life, and cognitive function, were similar. OHS and OHAD had similar treatment responses in these parameters after 3 months of PAP therapy.Nocturnal ventilatory support in OHS.

Heart Rate Variability Analysis in Obstructive Sleep Apnoea Patients with Daytime Sleepiness.

STUDY OBJECTIVES: Recent studies suggest sleepy patients with OSA are at higher risk for incident cardiovascular disease. This study assessed cardiac autonomic function in sleepy versus non-sleepy patients with obstructive sleep apnoea (OSA) using heart rate variability (HRV) analysis. We hypothesised that HRV profiles of sleepy patients would indicate higher cardiovascular risk. METHODS: Electrocardiograms (ECG) derived from polysomnograms (PSG) collected by the Sydney Sleep Biobank were used to study HRV in groups of sleepy (ESS≥10) and non-sleepy OSA patients (ESS<10). HRV parameters were averaged across available ECG signal during N2 sleep. RESULTS: A total of 421 patients were evaluated, with mean age of 54 (14) years, body mass index (BMI) of 33 (9) kg/m2, apnoea hypopnoea index (AHI) of 21 (28) events/h and, 66% male. The sleepy group consisted of 119 patients, and the non-sleepy group 302 patients. Sleepy patients exhibited lower HRV values for: root mean square successive difference (RMSSD, p= 0.028); total power (TP, p= 0.031); absolute low frequency (LF, p= 0.045); and high frequency (HF, p= 0.010) power compared to Non-Sleepy patients. Sleepy patients with moderate to severe OSA exhibited lower HRV values for: (RMSSD, p= 0.045; TP, p= 0.052) ; absolute LF (p= 0.051); and HF power (p= 0.025). There were no differences in other time and frequency domain HRV markers. CONCLUSIONS: This study shows a trend towards parasympathetic withdrawal in sleepy OSA patients, particularly in moderate to severe cases, lending mechanistic support to the link between the sleepy phenotype and CVD risk in OSA.

Online Education Improves Confidence in Mechanical Insufflation-Exsufflation.

BACKGROUND: Mechanical insufflation-exsufflation (MI-E) is a cough augmentation technique used to support people with an ineffective cough. MI-E can be complex due to the number of different pressure, flow, and temporal setting adjustments needed to optimize cough efficacy. Many clinicians identify inadequate training, limited experience, and low confidence as barriers to MI-E use. The purpose of this study was to determine if an online education course could improve confidence and competence in the delivery of MI-E. METHODS: An e-mail invitation to participate was disseminated to physiotherapists with a caseload that involved airway clearance for adults. The exclusion criteria were self-reported confidence and clinical expertise in MI-E. The education was created by physiotherapists with extensive experience in the provision of MI-E. The education material reviewed theoretical and practical components and was designed to take 6 h to complete. Physiotherapists were randomized to either the intervention group, who had 3 weeks of access to the education or the control group who received no intervention. Respondents in both groups completed a baseline and a post-intervention questionnaire by using visual analog scales, 0 to 10, with the primary outcomes being confidence in the prescription and confidence in the application of MI-E. Ten multiple-choice questions that covered key components of MI-E fundamentals were also completed at baseline and post-intervention. RESULTS: The intervention group had a significant improvement in the visual analog scale after the education period with a between-group difference of mean 3.6 (95% CI 4.5 to 2.7) for prescription confidence and mean 2.9 (95% CI 3.9 to 1.9) for application confidence. There was also an improvement in the multiple-choice questions with a between-group difference of mean 3.2 (95% CI 4.3 to 2). CONCLUSIONS: Access to an evidence-based online education course improved confidence in the prescription and application of MI-E, and may be a valuable tool for training clinicians in the application of MI-E.

Cardiopulmonary coupling and serum cardiac biomarkers in obesity hypoventilation syndrome and obstructive sleep apnea with morbid obesity.

STUDY OBJECTIVES: The main cause of death in patients with obesity hypoventilation syndrome (OHS) is cardiac rather than respiratory failure. Here, we investigated autonomic-respiratory coupling and serum cardiac biomarkers in patients with OHS and obstructive sleep apnea (OSA) with comparable body mass index and apnea-hypopnea index. METHODS: Cardiopulmonary coupling (CPC) and cyclic variation of heart rate analysis was performed on the electrocardiogram signal from the overnight polysomnogram. Cardiac serum biomarkers were obtained in patients with OHS and OSA with a body mass index > 40 kg/m2. Samples were obtained at baseline and after 3 months of positive airway pressure (PAP) therapy in both groups. RESULTS: Patients with OHS (n = 15) and OSA (n = 36) were recruited. No group differences in CPC, cyclic variation of heart rate, and serum biomarkers were observed at baseline and after 3 months of PAP therapy. An improvement in several CPC metrics, including the sleep apnea index, unstable sleep (low-frequency coupling and elevated low-frequency coupling narrow band), and cyclic variation of heart rate were observed in both groups with PAP use. However, distinct differences in response characteristics were noted. Elevated low-frequency coupling narrow band coupling correlated with highly sensitive troponin-T (P < .05) in the combined cohort. Baseline highly sensitive troponin-T inversely correlated with awake oxygen saturation in the OHS group (P < .05). CONCLUSIONS: PAP therapy can significantly improve CPC stability in patients with obesity with OSA or OHS, with key differences. Elevated low-frequency coupling narrow band may function as a surrogate biomarker for early subclinical cardiac disease. Low awake oxygen saturation could also increase this biomarker in OHS. CLINICAL TRIAL REGISTRATION: Registry: Australian New Zealand Clinical Trials Registry; Name: Obesity Hypoventilation Syndrome and Neurocognitive Dysfunction; URL: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=367492; Identifier: ACTRN12615000122550. CITATION: Sivam S, Wang D, Wong KKH, et al. Cardiopulmonary coupling and serum cardiac biomarkers in obesity hypoventilation syndrome and obstructive sleep apnea with morbid obesity. J Clin Sleep Med. 2022;18(4):1063-1071.

Cardiovascular disease in obesity hypoventilation syndrome - A review of potential mechanisms and effects of therapy.

Cardiovascular disease is common in patients with obesity hypoventilation syndrome (OHS) and accounts in part for their poor prognosis. This narrative review article examines the epidemiology of cardiovascular disease in obesity hypoventilation syndrome, explores possible contributing factors and the effects of therapy. All studies that included cardiovascular outcomes and biomarkers were included. Overall, there is a higher burden of cardiovascular disease and cardiovascular risk factors among patients with obesity hypoventilation syndrome. In addition to obesity and sleep-disordered breathing, there are several other pathophysiological mechanisms that contribute to higher cardiovascular morbidity and mortality in OHS. There is evidence emerging that positive airway pressure therapy and weight loss have beneficial effects on the cardiovascular system in obesity hypoventilation syndrome patients, but further research is needed to clarify whether this translates to clinically important outcomes.

Prevalence of chronic kidney disease in obesity hypoventilation syndrome and obstructive sleep apnoea with severe obesity.

PURPOSE: Chronic kidney disease (CKD) is common in severe obstructive sleep apnoea (OSA), however prevalence in obesity hypoventilation syndrome (OHS) is not known. This study sought to compare prevalence of CKD in OHS and equally obese OSA patients with comparable apnoea hypopnoea indexes (AHI), and secondarily examine the impact of positive airway pressure (PAP) therapy on CKD parameters. METHODS: Estimated Glomerular Filtration Rate (eGFR) and spot urine protein creatinine ratio (PCR) were obtained in patients with OHS (Partial pressure of carbon dioxide, PaCO2 > 45 mmHg) and OSA (AHI > 20 events per hour, PaCO2 < 45 mmHg) with a body mass index (BMI) > 40 kg/m2. Samples were obtained at baseline and after three months of PAP in both groups. RESULTS: Patients with OHS (n = 15, PaCO2 49 mmHg; daytime oxygen saturation, SpO2 94%; total sleep time with SpO2<90%, T90 308min) and OSA (n = 36, PaCO2 40 mmHg, SpO2 96%, T90 140min) were recruited. Stage 1-3 kidney function was present in 7 (46%) and 8 (22%) patients with OHS and OSA respectively (p = 0.08). Mean PCR was higher in OHS than OSA (23 ± 29 v 10 ± 6 mg/mmol; p = 0.03), while the prevalence of proteinuria was not different (40% v 19%, p = 0.19). Proteinuria was not significantly altered by three months of PAP. Moderate associations were demonstrated between eGFR, PaCO2, awake SpO2 and/or HbA1c (r > 0.5, p < 0.05) in OHS. CONCLUSION: The prevalence of CKD, primarily early-stage with proteinuria, is at least as frequent in OHS as it is in OSA, if not worse. Markers of CKD were not significantly impacted by PAP therapy.

Long-Term Noninvasive Ventilation in Chronic Stable Hypercapnic Chronic Obstructive Pulmonary Disease. An Official American Thoracic Society Clinical Practice Guideline.

Background: Noninvasive ventilation (NIV) is used for patients with chronic obstructive pulmonary disease (COPD) and chronic hypercapnia. However, evidence for clinical efficacy and optimal management of therapy is limited.Target Audience: Patients with COPD, clinicians who care for them, and policy makers.Methods: We summarized evidence addressing five PICO (patients, intervention, comparator, and outcome) questions. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to evaluate the certainty in evidence and generate actionable recommendations. Recommendations were formulated by a panel of pulmonary and sleep physicians, respiratory therapists, and methodologists using the Evidence-to-Decision framework.Recommendations:1) We suggest the use of nocturnal NIV in addition to usual care for patients with chronic stable hypercapnic COPD (conditional recommendation, moderate certainty); 2) we suggest that patients with chronic stable hypercapnic COPD undergo screening for obstructive sleep apnea before initiation of long-term NIV (conditional recommendation, very low certainty); 3) we suggest not initiating long-term NIV during an admission for acute-on-chronic hypercapnic respiratory failure, favoring instead reassessment for NIV at 2-4 weeks after resolution (conditional recommendation, low certainty); 4) we suggest not using an in-laboratory overnight polysomnogram to titrate NIV in patients with chronic stable hypercapnic COPD who are initiating NIV (conditional recommendation, very low certainty); and 5) we suggest NIV with targeted normalization of PaCO2 in patients with hypercapnic COPD on long-term NIV (conditional recommendation, low certainty).Conclusions: This expert panel provides evidence-based recommendations addressing the use of NIV in patients with COPD and chronic stable hypercapnic respiratory failure.

The Effect of Hospital Discharge with Empiric Noninvasive Ventilation on Mortality in Hospitalized Patients with Obesity Hypoventilation Syndrome. An Individual Patient Data Meta-Analysis.

Rationale: Hospitalized patients with acute-on-chronic hypercapnic respiratory failure due to obesity hypoventilation syndrome (OHS) have increased short-term mortality. It is unknown whether prescribing empiric positive airway pressure (PAP) at the time of hospital discharge reduces mortality compared with waiting for an outpatient evaluation (i.e., outpatient sleep study and outpatient PAP titration).Objectives: An international, multidisciplinary panel of experts developed clinical practice guidelines on OHS for the American Thoracic Society. The guideline panel asked whether hospitalized adult patients with acute-on-chronic hypercapnic respiratory failure suspected of having OHS, in whom the diagnosis has not yet been made, should be discharged from the hospital with or without empiric PAP treatment until the diagnosis of OHS is either confirmed or ruled out.Methods: A systematic review with individual patient data meta-analyses was performed to inform the guideline panel's recommendation. Grading of Recommendations, Assessment, Development, and Evaluation was used to summarize evidence and appraise quality.Results: The literature search identified 2,994 articles. There were no randomized trials. Ten studies met a priori study selection criteria, including two nonrandomized comparative studies and eight nonrandomized noncomparative studies. Individual patient data on hospitalized patients who survived to hospital discharge were obtained from nine of the studies and included a total of 1,162 patients (1,043 discharged with PAP and 119 discharged without PAP). Empiric noninvasive ventilation was prescribed in 91.5% of patients discharged on PAP, and the remainder received empiric continuous PAP. Discharge with PAP reduced mortality at 3 months (relative risk 0.12, 95% confidence interval 0.05-0.30, risk difference -14.5%). Certainty in the estimated effects was very low.Conclusions: Hospital discharge with PAP reduces mortality following acute-on-chronic hypercapnic respiratory failure in patients with OHS or suspected of having OHS. Well-designed clinical trials are needed to confirm this finding.

Advances in non-invasive positive airway pressure technology.

Non-invasive ventilation (NIV) has become the standard of care for patients with a range of respiratory and sleep breathing disorders. Technological advances have enabled the development of several newer modes of automatically adapting NIV suitable for patients with more complex breathing abnormalities that may be difficult to manage effectively with more traditional positive airway pressure therapy. These modes allow for more stable ventilation when fluctuating ventilation requirements occur such as in positional upper airway obstruction or state-related variations in respiratory mechanics and drive. Adaptive servoventilation (ASV) is designed for patients with periodic breathing and central apnoeas in whom carbon dioxide levels are normal to low, with the goal of therapy to dampen and stabilize ventilation. In contrast, volume-assured pressure support is used in diagnostic groups characterized by hypoventilation, where targeting an effective level of ventilation irrespective of sleep stage or body position is required. These newer modes have the potential to simplify and optimize ventilation, although at present there is no evidence that they are clinically superior to standard home ventilation techniques. The complexity and differences in algorithms and features of various device brands, along with a limited evidence base documenting longer term outcomes, complicate decisions around which patient phenotypes are best suited to these newer modes. In-built sensor and data storage capabilities of newer home ventilation devices provide the opportunity for earlier recognition of issues with ventilation and to guide corrective action. Further work is needed to determine how this impacts longer term clinical outcomes.

Slow-frequency electroencephalography activity during wake and sleep in obesity hypoventilation syndrome.

STUDY OBJECTIVE: Neurophysiological activity during wake and sleep states in obesity hypoventilation (OHS) and its relationship with neurocognitive function is not well understood. This study compared OHS with equally obese obstructive sleep apnea (OSA) patients, with similar apnea-hypopnea indices. METHODS: Resting wake and overnight sleep electroencephalography (EEG) recordings, neurocognitive tests, and sleepiness, depression and anxiety scores were assessed before and after 3 months of positive airway pressure (PAP) therapy in 15 OHS and 36 OSA patients. RESULTS: Pretreatment, greater slow frequency EEG activity during wake and sleep states (increased delta-alpha ratio during sleep, and theta power during awake) was observed in the OHS group compared to the OSA group. EEG slowing was correlated with poorer performance on the psychomotor vigilance task (slowest 10% of reciprocal reaction times, psychomotor vigilance test [PVT SRRT], primary outcome), and worse sleep-related hypoxemia measures in OHS. There was no between-group significant difference in PVT performance at pre or post-treatment. Similarly, despite both groups demonstrating improved sleepiness, anxiety and depression scores with PAP therapy, there were no differences in treatment response between the OSA and OHS groups. CONCLUSION: Patients with OHS have greater slow frequency EEG activity during sleep and wake than equally obese patients with OSA. Greater EEG slowing was associated with worse vigilance and lower oxygenation during sleep. CLINICAL TRIAL: This trial was registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12615000122550).

Evaluation and Management of Obesity Hypoventilation Syndrome. An Official American Thoracic Society Clinical Practice Guideline.

Background: The purpose of this guideline is to optimize evaluation and management of patients with obesity hypoventilation syndrome (OHS).Methods: A multidisciplinary panel identified and prioritized five clinical questions. The panel performed systematic reviews of available studies (up to July 2018) and followed the Grading of Recommendations, Assessment, Development, and Evaluation evidence-to-decision framework to develop recommendations. All panel members discussed and approved the recommendations.Recommendations: After considering the overall very low quality of the evidence, the panel made five conditional recommendations. We suggest that: 1) clinicians use a serum bicarbonate level <27 mmol/L to exclude the diagnosis of OHS in obese patients with sleep-disordered breathing when suspicion for OHS is not very high (<20%) but to measure arterial blood gases in patients strongly suspected of having OHS, 2) stable ambulatory patients with OHS receive positive airway pressure (PAP), 3) continuous positive airway pressure (CPAP) rather than noninvasive ventilation be offered as the first-line treatment to stable ambulatory patients with OHS and coexistent severe obstructive sleep apnea, 4) patients hospitalized with respiratory failure and suspected of having OHS be discharged with noninvasive ventilation until they undergo outpatient diagnostic procedures and PAP titration in the sleep laboratory (ideally within 2-3 mo), and 5) patients with OHS use weight-loss interventions that produce sustained weight loss of 25% to 30% of body weight to achieve resolution of OHS (which is more likely to be obtained with bariatric surgery).Conclusions: Clinicians may use these recommendations, on the basis of the best available evidence, to guide management and improve outcomes among patients with OHS.

Non-invasive ventilation versus oxygen therapy in cystic fibrosis: A 12-month randomized trial.

BACKGROUND AND OBJECTIVE: No published studies have examined the long-term effects of non-invasive ventilation (NIV) in cystic fibrosis (CF). Our primary aim was to determine if adults with CF and sleep desaturation were less likely to develop hypercapnia with NIV ± O2 compared to low-flow oxygen therapy (LFO2 ) or meet the criteria for failure of therapy over 12 months. We studied event-free survival, hospitalizations, lung function, arterial blood gases (ABG), sleep quality and health-related quality of life. METHODS: A prospective, randomized, parallel group study in adult patients with CF and sleep desaturation was conducted, comparing 12 months of NIV ± O2 to LFO2 . Event-free survival was defined as participants without events. Events included: failure of therapy with PaCO2 > 60 mm Hg, or increase in PaCO2 > 10 mm Hg from baseline, increases in TcCO2 > 10 mm Hg, lung transplantation or death. Outcomes were measured at baseline, 3, 6 and 12 months, including lung function, ABG, Pittsburgh Sleep Quality Inventory (PSQI), SF36 and hospitalizations. RESULTS: A total of 29 patients were randomized to NIV ± O2 (n = 14) or LFO2 (n = 15) therapy for 12 months. Of the 29 patients, 18 met the criteria for event-free survival over 12 months. NIV ± O2 group had 33% (95% CI: 5-58%) and 46% (95% CI: 10-68%) more event-free survival at 3 and 12 months than LFO2 group. No statistically significant differences were seen in spirometry, ABG, questionnaires or hospitalizations. CONCLUSION: NIV ± O2 during sleep increases event-free survival over 12 months in adults with CF. Further studies are required to determine which subgroups benefit the most from NIV.