[Congenital Central Hypoventilation Syndrome: neonatal diagnosis and management]. / Síndrome de Hipoventilación Central Congénito: diagnóstico y manejo neonatal.

Congenital Central Hypoventilation Syndrome (CCHS) is a rare genetic condition affecting the autonomic nervous system and respiratory center due to mutations in the PHOX2B gene, and it is associated with alveolar hypoventilation during sleep and sudden death. It requires early invasive mechanical ventilation (IMV). OBJECTIVE: To report a neonatal case successfully treated with non-invasive ventilatory support (NVS), avoiding tracheostomy. CLINICAL CASE: Full-term newborn, whose mother uses nocturnal NVS due to CCHS. During the transition period, she presented desaturations associated with hypercapnia and respiratory acidosis, without pulmonary involvement. She developed severe hypoventilation during sleep, with no respiratory effort, peripheral oxygen saturation (SpO2) < 80%, plus respiratory acidosis. While awake, she had good respiratory effort and normal SpO2 without assistance. Noninvasive continuous positive airway pressure and oxygen therapy worsened her condition while sleeping. Complete NVS with nasal interface and bi-level airway positive pressure, inspiratory/expiratory pressure 14-16/4 cm H2O, normalized SpO2 during sleep, and arterial blood gases while awake. Sequencing of the PHOX2B gene confirmed the presence of a heterozygous pathogenic variant with the 20/26 genotype. At 2 months of age, she was discharged maintaining NVS with nasal interface and 0 PEEP, achieving adequate neurodevelopment. CONCLUSION: We highlight the importance of genetic diagnosis of CCHS in neonates with clinical presentation of early alveolar hypoventilation, especially if there is a family history. We are not aware of other reports of neonatal onset in which NVS prevents IMV, in this potentially lethal pathology.

Congenital Central Hypoventilation Syndrome and Disorders of Control of Ventilation.

Congenital disorders of ventilatory control typically manifest as central apneas, periodic breathing, and hypoventilation in the neonatal period, but some may present at a later age. Obstructive apneas may be the initial presentation, and some may have associated autonomic nervous system dysfunction. Individuals with these disorders can have absent or impaired ventilatory and arousal responses to hypoxemia and hypercapnia. This article discusses the presentation, pathophysiology, evaluation, and management of congenital central hypoventilation syndrome, rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome, Prader-Willi syndrome, and myelomeningocele.

Central sleep apnea: emphasizing recognition and differentiation.

INTRODUCTION: Central sleep apnea (CSA) is a sleep-related breathing disorder in which the effort to breathe is intermittently diminished or absent. CSA is a common disorder among patients with different cardiovascular disorders, including heart failure. In addition, a growing number of medications have been shown to induce CSA and CSA can emerge after initiation of treatment for obstructive sleep apnea. Accumulating evidence shows that CSA is a heterogeneous disorder with individual differences in clinical and biological characteristics and/or underlying pathophysiological mechanisms. AREAS COVERED: This narrative review offers an overview of the diagnostic aspects and classification of CSA, with an emphasis on heart failure patients, patients with CSA due to a medication and treatment-emergent CSA. The importance of evaluation of prognostic biomarkers in patients with different types of CSA is discussed. This narrative review synthesizes literature on CSA sourced from the PubMed database up to February 2024. EXPERT OPINION: CSA presents a remarkably diverse disorder, with treatment modalities exhibiting potentially varied efficacy across its various phenotypes. This highlights the imperative for tailored management strategies that are rooted in phenotype classification.

[Adaptive servo-ventilation in patients with heart failure and sleep apnea: Insights from the ADVENT-HF trial].

Heart failure is strongly associated with obstructive and central sleep apnea. The landmark 2015 SERVE-HF trial showed that using adaptive servo-ventilation (ASV) for central sleep apnea (CSA) management was associated with an increased risk of all-cause and cardiovascular mortality among heart failure patients with reduced ejection fractions. Based on the result, the American Academy of Sleep Medicine and the European Society of Cardiology have recommended against the use of ASV for the treatment of CSA in patients with heart failure with an ejection fraction≤45%. Recently, the results from the ADVENT-HF trial have been formally published, indicating that ASV does not increase adverse outcomes and can improve patients' quality of life. Here, we go over these findings in detail.

Congenital central hypoventilation syndrome in korea: 20 years of clinical observation and evaluation of the ventilation strategy in a single center.

Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder characterized by hypoventilation due to impaired breathing control by the central nervous system and other symptoms of autonomic dysfunction. Mutations in paired-like homeobox 2 B (PHOX2B) are responsible for most cases of CCHS. Patients with CCHS have various phenotypes and severities, making the diagnosis difficult. This study aimed to present a comprehensive single-center experience of patients with CCHS, including key clinical features, treatment strategies, and outcomes. A retrospective chart review was performed for patients diagnosed with CCHS between January 2001 and July 2023 at Seoul National University Children's Hospital. Finally, we selected 24 patients and collected their demographic data, genotypes, ventilation methods, and clinical features related to autonomic dysfunction. The relationship between the clinical manifestations and genotypes was also examined. All patients used home ventilators, and tracheostomy was performed in 87.5% of patients. Fifteen (62.5%) patients had constipation and nine (37.5%) were diagnosed with Hirschsprung disease. Arrhythmia, endocrine dysfunction, and subclinical hypothyroidism were present in nine (37.5%), six patients (25.0%), and two patients (16.7%), respectively. A significant number of patients exhibited neurodevelopmental delays (19 patients, 79.2%). There was a correlation between the phenotype and genotype of PHOX2B in patients with CCHS. (r = 0.71, p < 0.001).   Conclusion: There was a positive correlation between paired-like homeobox 2 B mutations (especially the number of GCN repeats in the polyalanine repeat mutations sequence) and clinical manifestations. This study also demonstrated how initial treatment for hypoventilation affects neurodevelopmental outcomes in patients with CCHS. What is Known: • Congenital central hypoventilation syndrome is a rare genetic disorder characterized by hypoventilation and dysfunction of autonomic nervous system. • The disease-defining gene of CCHS is PHOX2B gene - most of the cases have heterozygous PARMs and the number of GCN triplets varies among the patients(20/24 - 20/33). What is New: • We have noted in the Korean patients with CCHS that there is a correlation between genotype (number of GCN repeats) and severity of phenotype. • National support for rare diseases allowed for a prompter diagnosis of patients with CCHS in Korean population.

Lamentations in the night: A systematic review on catathrenia.

Catathrenia is a loud expiratory moan during sleep that is a social embarrassment and is sometimes confused with central apnea on polysomnography. It affects about 4% of adults, but cases are rarely referred to sleep centers. Catathrenia affects males and females, children and adults, who are usually young and thin. A "typical" catathrenia begins with a deep inhalation, followed by a long, noisy exhalation, then a short, more pronounced exhalation, followed by another deep inhalation, often accompanied by arousal. The many harmonics of the sound indicate that it is produced by the vocal cords. It is often repeated in clusters, especially during REM sleep and at the end of the night. It does not disturb the sleepers, but their neighbors, and is associated with excessive daytime sleepiness in one-third of cases. The pathophysiology and treatment of typical catathrenia are still unknown. Later, a more atypical catathrenia was described, consisting of episodes of short (2 s), regular, semi-continuous expiratory moans during NREM sleep (mainly in stages N1 and N2) and REM sleep, often in people with mild upper airway obstruction. This atypical catathrenia is more commonly reduced by positive airway pressure and mandibular advancement devices that promote vertical opening.

Persistent and symptomatic periodic breathing beyond the neonatal period in full-term infants: A case series.

INTRODUCTION: Periodic breathing (PB) is considered physiological in the neonatal period and usually disappears in the first months of life. There are few data available on persistent PB after the neonatal period. The objective of this study was to characterize infants born at term with persistent PB after the age of 1 month through polysomnography (PSG) performed during symptoms. METHODS: This retrospective case series included infants born at term between 2012 and 2021, without an underlying disease, who presented with symptoms of persistent PB during a PSG. Persistent PB was defined as more than 1 % of total sleep time (TST) of PB after 1 month of life, and PB was defined as a succession of at least three episodes of central apnea lasting more than 3 s and separated by less than 20 s of normal breathing. RESULTS: A total of 10 infants born at term were included. They underwent PSG for brief resolved unexplained events, desaturation, pauses in breathing, cyanosis, and/or signs of respiratory distress. The percentage of TST spent with PB was 18.1 % before 3 months of age (n = 7), and 4.7 % between 3 and 6 months of age (n = 10). During the first PSG, ≥3 % of desaturation events were observed in 77-100 % of the PB episodes. At the first PSG, nine of the 10 infants had an obstructive apnea-hypopnea index of >10/h and five of 10 infants had a central apnea index of >5/h. Gastroesophageal reflux (GER) was suspected in eight infants. All infants showed improvement in the initial symptoms during the first year of life. CONCLUSION: This study presents cases of persistent and symptomatic PB after 1 month of life in infants born at term. The interesting finding was the presence of obstructive sleep apnea syndrome and/or central apnea syndrome in the majority of children, along with GER.

Tracheostomy and inpatient outcomes among children with congenital central hypoventilation syndrome: A kids' inpatient database study.

STUDY OBJECTIVES: Congenital central hypoventilation syndrome (CCHS) is a rare disease predisposing children to respiratory failure due to abnormal ventilatory drive. Variability in hypoventilation and respiratory support need have been reported. We aim to identify clinical variables associated with incident tracheostomy and common etiologies of hospitalization among children with CCHS. METHODS: Hospital discharge records were obtained for children (<21 years) with CCHS hospitalized between 2006 and 2019 from the Kid's Inpatient Database. Primary diagnostic categories for hospitalizations with CCHS were summarized. Multivariable logistic regression models were used to explore risk factors associated with incident tracheostomy. RESULTS: Among 2404 hospitalizations with CCHS, 133 (5.5%) had incident tracheostomy, 1230 (51.2%) had established tracheostomy, and 1041 (43.3%) had no tracheostomy. Compared with children without tracheostomy, those with incident tracheostomy were younger, had a history of prematurity, congenital heart disease, laryngeal, glottic, and subglottic stenosis (LGSS), congenital airway anomalies, neuromuscular weakness, gastroesophageal reflux disease. Children without tracheostomy had higher mortality than those with tracheostomy status (2.19% vs. 0.66%). Multivariable-adjusted analyses showed that incident tracheostomy was associated with infancy (0-1 years), neuromuscular weakness, and congenital heart disease. Most common diagnostic categories include (1) diseases of the respiratory system (30.23%), (2) injury and poisoning (9.35%), and (3) diseases of the nervous system and sense organs (6.71%). CONCLUSIONS: Children with CCHS who received incident tracheostomy are more likely to be younger and with LGSS, neuromuscular weakness and congenital heart disease. Clinicians should be aware of these risk factors representing more severe CCHS with earlier manifestation needing tracheostomy. Higher mortality among nontracheostomy group highlights the need for considering tracheostomy in caring for children with CCHS.

Central sleep apnoea: not just one phenotype.

Recent scientific findings in the field of sleep disordered breathing have characterised a variety of phenotypes in obstructive sleep apnoea. These findings have prompted investigations aiming to achieve a more precise differentiation and description of the entities of central sleep apnoea (CSA). There is increasing evidence for the heterogeneity of CSA in terms of underlying aetiology, pathophysiological concepts, treatment response and outcome. Assigning patients to these phenotypes allows for the selection of individualised therapies. Major pathophysiological characteristics include loop gain, apnoeic threshold, breathing regulation and neuromuscular mechanics. Chronic heart failure is the most important underlying disease, leading to nonhypercapnic CSA based on increased loop and controller gain. Although many questions remain, this review tries to describe the current knowledge on the pathophysiology of the clinical entities. The description of prognostic aspects may guide treatment indication and the selection of pharmacotherapy and invasive options. In addition, the paper provides an update on the current understanding of adaptive servo-ventilation and its role in the treatment of CSA.

Airway obstruction in two children with congenital central hypoventilation syndrome and review of the literature.

Congenital central hypoventilation syndrome (CCHS) is an autosomal dominant disease that is caused by heterozygous mutations in the paired-like homeobox 2B gene (PHOX2B). Madani et al. described an abnormally high degree of not only central apnea but also obstructive and mixed apnea in Phox2b27Ala/+newborn mice. Newborns with CCHS must undergo polysomnography for obstructive respiratory events in order to guide the optimal ventilation strategy if oxygen desaturation, bradycardia, and malaise persist under noninvasive ventilation. Newborns and infants with CCHS must be systematically tested for obstructive apnea, especially in cases of inefficient noninvasive ventilation.

Case report of hypoglossal nerve stimulation therapy failure due to significant underlying central sleep apnea.

Hypoglossal nerve stimulation is indicated for obstructive sleep apnea but is ineffective in treating central sleep apnea. We describe 2 patients implanted with hypoglossal nerve stimulation after being diagnosed with obstructive sleep apnea at outside sleep laboratories and failing a trial of continuous positive airway pressure therapy. Despite successful hypoglossal nerve stimulation implantation, the patients continued to have persistent symptoms with residual apnea-hypopnea indices above 25 events/h. Although obstructive sleep apnea was the presenting diagnosis, we discovered a significant central sleep apnea component in the original diagnostic sleep data upon careful review. One patient was confirmed to have a central sleep apnea-predominant sleep disorder and improved with adaptive servo-ventilation therapy. The other was diagnosed with central sleep apnea and severe periodic limb movement disorder, and improved with medication. Based on these sleep apnea cases, we propose guidelines emphasizing the importance of reviewing basic clinical information upon treatment failure and initiating multidisciplinary collaboration early in the treatment course. CITATION: Banerjee D, Lee C-H, Im K. Case report of hypoglossal nerve stimulation therapy failure due to significant underlying central sleep apnea. J Clin Sleep Med. 2024;20(6):1003-1007.

Association of Sex With Cardiovascular Outcomes in Heart Failure Patients With Obstructive or Central Sleep Apnea.

BACKGROUND: This study investigated the association of sex with cardiovascular outcomes in a prospective cohort of patients with heart failure (HF) with obstructive sleep apnea or central sleep apnea. METHODS AND RESULTS: Patients were screened for sleep apnea on admission using multichannel cardiopulmonary monitoring from May 2015 to July 2018. The primary outcome was a composite of cardiovascular death or unplanned hospitalization for worsening HF. Ultimately, 453 patients with HF with obstructive sleep apnea or central sleep apnea were included; 71 (15.7%) and 382 (84.3%) were women and men, respectively. During a median follow-up of 2.33 years, 248 (54.7%) patients experienced the primary outcome. In the overall population, after adjusting for potential confounders, women had an increased risk of the primary outcome (66.2% versus 52.6%; hazard ratio [HR], 1.47 [95% CI, 1.05-2.04]; P=0.024) and HF rehospitalization (62.0% versus 46.6%; HR, 1.55 [95% CI, 1.10-2.19]; P=0.013) compared with men but a comparable risk of cardiovascular death (21.1% versus 23.3%; HR, 0.78 [95% CI, 0.44-1.37]; P=0.383). Likewise, in patients with HF with obstructive sleep apnea, women had a higher risk of the primary outcome (81.8% versus 46.3%, HR, 2.37 [95% CI, 1.28-4.38]; P=0.006) and HF rehospitalization (81.8% versus 44.7%, HR, 2.46 [95% CI, 1.32-4.56], P=0.004). However, in patients with HF with central sleep apnea, there was no statistically significant difference between women and men. CONCLUSIONS: In hospitalized patients with HF, female sex was associated with an increased risk of the primary outcome and HF rehospitalization, especially in those with obstructive sleep apnea. Screening for sleep apnea should be emphasized to improve the prognosis. REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02664818.

The prevalence and polysomnographic characteristics of treatment-emergent central sleep apnea with obstructive sleep apnea.

PURPOSE: To investigate the prevalence of treatment-emergent central sleep apnea (TECSA) in individuals with obstructive sleep apnea syndrome (OSAS) during continuous positive airway pressure (CPAP) titration and assess their polysomnographic characteristics. METHODS: A total of 116 patients with OSAS who underwent full-night CPAP titration at the Sleep Laboratory of Adana City Research and Education Hospital from September 2017 to January 2018 were recruited for the study. The patients' polysomnographic data related to respiratory events and sleep stages were reviewed in a retrospective manner. RESULTS: While on CPAP titration, 20 of the 116 patients developed central sleep apnea (CSA). The prevalence of TECSA in the patients with OSAS was 17.2%, being separately determined as 16.3% and 2.2% for the male and female patients, respectively. In the baseline PSG, the groups did not statistically significantly differ in relation to the apnea hypopnea index (AHI), central apnea index (CAI), arousal index (AI), or oxygen desaturation index (ODI). However, the TECSA group had a significantly higher mean oxygen saturation value compared to the non-TECSA group (p = 0.01). The total AHI, CAI, and AI values of the TECSA group were significantly higher during the whole CPAP titration compared to the non-TECSA group. No significant difference was observed in the comparison of the two groups in relation to the titration pressure and ODI. CONCLUSION: TECSA is a phenomenon that can occur with obstructive sleep apnea treatment and mostly regress spontaneously following appropriate CPAP treatment. TECSA is observed at different rates of prevalence. In this study, the prevalence of TECSA was higher than previously reported.

Images: Atypical presentation of congenital central hypoventilation syndrome in an infant with central and obstructive sleep apnea.

Congenital central hypoventilation syndrome (CCHS), a rare disease caused by paired-like homeobox 2B variants, affects control of breathing. We report on a 21-month-old boy with CCHS caused by a novel nonpolyalanine repeat mutation, neuroblastoma, severe obstructive and central sleep apnea, and sleep-related hypoxemia without hypoventilation. At 10 months, due to persistent central sleep apnea during serial polysomnography, bilevel positive airway pressure therapy was initiated despite the absence of hypoventilation. Nonpolyalanine repeat mutations are associated with severe phenotypes requiring continuous assisted ventilation, Hirschsprung's disease, and neural crest tumors; however, our patient had a relatively milder respiratory phenotype requiring sleep-only assisted ventilation without tracheostomy. Although alveolar hypoventilation is the hallmark of CCHS, our patient lacked hypoventilation. Bilevel positive airway pressure could be considered in some infants with CCHS requiring sleep-only assisted ventilation for tracheostomy avoidance. Our case demonstrates the expanding phenotypic spectrum in CCHS and the importance of formulating an individualized care plan. CITATION: Fain ME, Raghunandan S, Pencheva B, Leu RM, Kasi AS. Images: atypical presentation of congenital central hypoventilation syndrome in an infant with central and obstructive sleep apnea. J Clin Sleep Med. 2024;20(3):478-481.

Transvenous phrenic nerve stimulation for treating central sleep apnea may regulate sleep microstructure.

STUDY OBJECTIVES: To assess the impact of transvenous phrenic nerve stimulation (TPNS) on non-rapid eye movement sleep microstructure quantified by cyclic alternating pattern (CAP) in individuals with central sleep apnea (CSA). METHODS: We analyzed baseline and 6-month follow-up overnight polysomnograms (PSG) in 134 CSA patients enrolled in the remede System Pivotal Trial implanted with TPNS randomized (1:1) to neurostimulation (treatment group) or no stimulation (control group). Differences in CAP rate, A1 index, and A2+A3 index between study arms at follow-up were assessed using Analysis of Covariance adjusted for baseline values. RESULTS: On follow-up PSG, the treatment group showed a decrease in the frequency of A2+A3 phases compared to controls (-5.86 ± 11.82 vs. 0.67 ± 15.25, p = 0.006), while the frequency of A1 phases increased more in the treatment group (2.57 ± 11.67 vs. -2.47 ± 10.60, p = 0.011). The change in CAP rate at follow-up was comparable between study arms. CONCLUSIONS: TPNS treatment for central sleep apnea may affect sleep microstructure. Brief phases of rapid cortical activity appear to be replaced by short phases of slower cortical activity, which may promote sleep continuity. Further investigations are warranted to elucidate the mechanisms underlying the effect of TPNS on CAP.

Characteristics and outcomes in children with congenital central hypoventilation syndrome on long-term mechanical ventilation in the Netherlands.

Congenital central hypoventilation syndrome (CCHS) is a rare condition characterized by central hypoventilation, leading to the majority of patients being dependent on ventilatory support during sleep. This condition is often accompanied by various associated symptoms, due to a PHOX2B gene variant involved in neuronal crest cell migration. This study is the first to review the characteristics and outcomes in children with CCHS on long-term mechanical ventilation in the Netherlands. We performed a retrospective study of all CCHS patients treated in the 4 Centers of Home Mechanical Ventilation of the University Medical Centers in the Netherlands from 2000 till 2022 by collecting information from the electronic medical records, documented during follow-up. We included 31 patients, out of which 27 exhibited a known genetic profile associated with CCHS, while no PHOX2B variant was identified in the remaining patients. Among the 27 patients with known genetic profiles, 10 patients had a non-polyalanine repeat expansion mutation (NPARM), followed by 20/27, 20/25, and 20/26 polyalanine repeat expansion mutations (PARMs) in descending order. The most common presentation involved respiratory failure or apneas during the neonatal period with an inability to wean off ventilation. The majority of patients required ventilatory support during sleep, with four patients experiencing life-threatening events related to this dependency. Daily use of ventilatory support varied among different genetic profiles. All genotypes reported comorbidities, with Hirschsprung's disease and cardiac arrhythmias being the most reported comorbidities. Notably, Hirschprung's disease was exclusively observed in patients with a 20/27 PHOX2B variant. CONCLUSION: Our study results suggest that in our cohort, the genotype is not easily associated to the phenotype in CCHS. Consistent with these findings and international literature, we recommend a thorough annual evaluation for all patients with CCHS to ensure optimal management and follow-up. WHAT IS KNOWN: • The majority of CCHS patients are dependent on ventilatory support. • Variants in the PHOX2B gene are responsible for the characteristics of CCHS. WHAT IS NEW: • This study provides insight into the clinical course and long-term outcomes of CCHS patients in the Netherlands. • In CCHS, the genotype is not easily associated with the phenotype, requiring a thorough life-long follow-up for all patients.

Analysis by sex of safety and effectiveness of transvenous phrenic nerve stimulation.

PURPOSE: Little is known about sex differences in the treatment of central sleep apnea (CSA). Our post hoc analysis of the remede System Pivotal Trial aimed to determine sex-specific differences in the safety and effectiveness of treating moderate to severe CSA in adults with transvenous phrenic nerve stimulation (TPNS). METHODS: Men and women enrolled in the remede System Pivotal Trial were included in this post hoc analysis of the effect of TPNS on polysomnographic measures, Epworth Sleepiness Scale, and patient global assessment for quality of life. RESULTS: Women (n = 16) experienced improvement in CSA metrics that were comparable to the benefits experienced by men (n = 135), with central apneas being practically eliminated post TPNS. Women experienced improvement in sleep quality and architecture that was comparable to men post TPNS. While women had lower baseline apnea hypopnea index than men, their quality of life was worse at baseline. Additionally, women reported a 25-percentage point greater improvement in quality of life compared to men after 12 months of TPNS therapy. TPNS was found to be safe in women, with no related serious adverse events through 12 months post-implant, while men had a low rate of 10%. CONCLUSION: Although women had less prevalent and less severe CSA than men, they were more likely to report reduced quality of life. Transvenous phrenic nerve stimulation may be a safe and effective tool in the treatment of moderate to severe CSA in women. Larger studies of women with CSA are needed to confirm our findings. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01816776; March 22, 2013.

Adaptive servo-ventilation for sleep-disordered breathing in patients with heart failure with reduced ejection fraction (ADVENT-HF): a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial.

BACKGROUND: In patients with heart failure and reduced ejection fraction, sleep-disordered breathing, comprising obstructive sleep apnoea (OSA) and central sleep apnoea (CSA), is associated with increased morbidity, mortality, and sleep disruption. We hypothesised that treating sleep-disordered breathing with a peak-flow triggered adaptive servo-ventilation (ASV) device would improve cardiovascular outcomes in patients with heart failure and reduced ejection fraction. METHODS: We conducted a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial of peak-flow triggered ASV in patients aged 18 years or older with heart failure and reduced ejection fraction (left ventricular ejection fraction ≤45%) who were stabilised on optimal medical therapy with co-existing sleep-disordered breathing (apnoea-hypopnoea index [AHI] ≥15 events/h of sleep), with concealed allocation and blinded outcome assessments. The trial was carried out at 49 hospitals in nine countries. Sleep-disordered breathing was stratified into predominantly OSA with an Epworth Sleepiness Scale score of 10 or lower or predominantly CSA. Participants were randomly assigned to standard optimal treatment alone or standard optimal treatment with the addition of ASV (1:1), stratified by study site and sleep apnoea type (ie, CSA or OSA), with permuted blocks of sizes 4 and 6 in random order. Clinical evaluations were performed and Minnesota Living with Heart Failure Questionnaire, Epworth Sleepiness Scale, and New York Heart Association class were assessed at months 1, 3, and 6 following randomisation and every 6 months thereafter to a maximum of 5 years. The primary endpoint was the cumulative incidence of the composite of all-cause mortality, first admission to hospital for a cardiovascular reason, new onset atrial fibrillation or flutter, and delivery of an appropriate cardioverter-defibrillator shock. All-cause mortality was a secondary endpoint. Analysis for the primary outcome was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01128816) and the International Standard Randomised Controlled Trial Number Register (ISRCTN67500535), and the trial is complete. FINDINGS: The first and last enrolments were Sept 22, 2010, and March 20, 2021. Enrolments terminated prematurely due to COVID-19-related restrictions. 1127 patients were screened, of whom 731 (65%) patients were randomly assigned to receive standard care (n=375; mean AHI 42·8 events per h of sleep [SD 20·9]) or standard care plus ASV (n=356; 43·3 events per h of sleep [20·5]). Follow-up of all patients ended at the latest on June 15, 2021, when the trial was terminated prematurely due to a recall of the ASV device due to potential disintegration of the motor sound-abatement material. Over the course of the trial, 41 (6%) of participants withdrew consent and 34 (5%) were lost to follow-up. In the ASV group, the mean AHI decreased to 2·8-3·7 events per h over the course of the trial, with associated improvements in sleep quality assessed 1 month following randomisation. Over a mean follow-up period of 3·6 years (SD 1·6), ASV had no effect on the primary composite outcome (180 events in the control group vs 166 in the ASV group; hazard ratio [HR] 0·95, 95% CI 0·77-1·18; p=0·67) or the secondary endpoint of all-cause mortality (88 deaths in the control group vs. 76 in the ASV group; 0·89, 0·66-1·21; p=0·47). For patients with OSA, the HR for all-cause mortality was 1·00 (0·68-1·46; p=0·98) and for CSA was 0·74 (0·44-1·23; p=0·25). No safety issue related to ASV use was identified. INTERPRETATION: In patients with heart failure and reduced ejection fraction and sleep-disordered breathing, ASV had no effect on the primary composite outcome or mortality but eliminated sleep-disordered breathing safely. FUNDING: Canadian Institutes of Health Research and Philips RS North America.

Effect of Facemask in Congenital Central Hypoventilation Syndrome.

INTRODUCTION: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder with a mutation in the PHOX2B gene. Patients need ventilatory support by noninvasive ventilation or tracheostomy to treat alveolar hypoventilation. Patients with CCHS have a defect in chemosensitivity signal integration. Recently, due to the COVID-19 pandemic, the entire world has had to get used to wearing medical masks (MM). OBJECTIVES: The aim of the study was to evaluate the effect of an MM on gas exchange and to determine the role of central and peripheral chemoresponsiveness on the partial pressure of transcutaneous carbon dioxide (PtcCO2) in patients with CCHS wearing an MM. METHODS: This study was based on the analysis of recordings obtained without and with an MM during hospitalization and was conducted to assess the impact of MM on PtcCO2 and SpO2 recordings with the SenTec Digital Monitor and their relationships with peripheral CO2 chemosensitivity obtained during tidal breathing measurement and with the hypercapnic hyperoxic ventilatory response. RESULTS: Sixteen patients were included (13 boys) and were 10.2 (7.5; 18.5) years old. The use of an MM had a negative impact on gas exchange in patients with CCHS. The median PtcCO2 increased significantly. Peripheral chemosensitivity correlated with MM-induced PtcCO2 changes (R = -0.72, p = 0.005), but central chemosensitivity (the hypercapnic ventilator response slope) did not (R = -0.22, p = 0.510). CONCLUSION: The use of an MM had a negative impact on gas exchange in patients with CCHS.