Changes in cognitive function and daytime sleepiness in patients with chronic heart failure and Cheyne-Stokes respiration with adaptive servo ventilation treatment.

STUDY OBJECTIVES: Cheyne - Stokes respiration (CSR) is prevalent in patients with chronic heart failure (CHF). Adaptive Servo Ventilation (ASV) alleviates CSR and improves objective sleep quality. We investigated the effects of ASV on neurocognitive function in the symptomatic phenotype of patients with CSR and CHF. METHODS: This case series included patients diagnosed with stable CHF (NYHA ≥ II) and CSR (N = 8). Sleep and neurocognitive function were assessed at baseline and after 1- and 6-months following initiation of ASV treatment. RESULTS: In CHF patients (n = 8, median age 78.0[64.5-80.8] years and BMI 30.0[27.0-31.5] kg/m2, median ejection fraction 30[24-45]%, Epworth Sleepiness Scale (ESS) score 11.5[9.0-15.0]), ASV markedly improved respiration during sleep (Apnea-Hypopnea Index (AHI) 44.1[39.0-51.5]n/h at baseline, 6.3[2.4-9.7]n/h at 6 months treatment, respectively, p < 0.01). The 6-min-walk test distance increased by treatment from (295.0[178.8-385.0] m to 356.0[203.8-495.0] m (p = 0.05)). Sleep structure was modified, and Stage 3 increased markedly from 6.4[1.7-20.1] % to 20.8[14.2-25.3] %, p < 0.02). Sleep latency in the Maintenance of Wakefulness Test increased from 12.0[6.0-30.0] min to 26.3[12.0-30.0] min, (p = 0.04). In the Attention Network Test, evaluating neurocognition, the number of lapses decreased from 6.0[1.0-44.0] to 2.0[0.3-8.0], (p = 0.05) and the overall number of responses to a preset stimulus increased after treatment (p = 0.04). CONCLUSIONS: ASV treatment in CHF patients with CSR may improve sleep quality, neurocognition and daytime performance.

Impact of transcatheter edge-to-edge mitral valve repair on central sleep apnoea.

AIMS: Sleep-disordered breathing (SDB) and its subtype central sleep apnoea (CSA) are highly prevalent in patients with heart failure and associated with worse prognosis. Whereas pharmacological therapy of heart failure has been shown to ameliorate CSA, results from previous studies on the effect of mitral regurgitation therapy on SDB are contradicting. The aim of this study was to assess the impact of transcatheter edge-to-edge mitral valve repair (TEER) on prevalence and severity of CSA. METHODS AND RESULTS: We enrolled 47 patients undergoing TEER for symptomatic mitral regurgitation in a prospective study. Secondary mitral regurgitation and left ventricular ejection fraction < 50% were present in 79% and 68% of patients, respectively. Respiratory polygraphy was performed before TEER in a compensated condition and four weeks after the procedure. 34 patients completed the follow-up. At baseline, 19 (56%) patients showed moderate-to-severe SDB, of whom 13 (68%) were classified as CSA. Both apnoea-hypopnoea index and percentage of recorded time spent in Cheyne-Stokes respiration strongly decreased from baseline to follow-up (median [IQR] 16 [7-30] vs. 7 [4-15] /h, p = 0.007; 6 [0-34] vs. 0 [0-8] %, p = 0.008). Median relative reduction of central apnoea index was 75% (p = 0.023), while obstructive apnoea index did not change significantly. Increase in stroke volume after TEER and high systolic pulmonary artery pressure at baseline predicted a > 50% reduction of both Apnoea-hypopnoea index and Cheyne-Stokes respiration. CONCLUSION: TEER is associated with a significant short-term reduction of CSA and Cheyne-Stokes respiration in high-risk patients, strengthening its value as an effective treatment option for advanced heart failure.

Treatment of Cheyne-Stokes Respiration in Heart Failure with Adaptive Servo-Ventilation: An Integrative Model.

The SERVE-HF (Treatment of Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients with Heart Failure) multicenter trial found a small but significant increase in all-cause and cardiovascular mortality in patients assigned to adaptive servo-ventilation (ASV) versus guideline-based medical treatment. To better understand the physiological underpinnings of this clinical outcome, we employ an integrative computer model to simulate congestive heart failure with Cheyne-Stokes respiration (CHF-CSR) in subjects with a broad spectrum of underlying pathogenetic mechanisms, as well as to determine the in silico changes in cardiopulmonary and autonomic physiology resulting from ASV. Our simulation results demonstrate that while the elimination of CSR through ASV can partially restore cardiorespiratory and autonomic physiology toward normality in the vast majority of CHF phenotypes, the degree of restoration can be highly variable, depending on the combination of CHF mechanisms in play. The group with the lowest left ventricular ejection fraction (LVEF) appears to be most vulnerable to the potentially adverse effects of ASV, but the level of pulmonary capillary wedge pressure (PCWP) plays an important role in determining the nature of these effects.

Sleep Breathing Disorders in Heart Failure.

Sleep-disordered breathing (SDB), including obstructive sleep apnea, central sleep apnea (CSA), and Cheyne-Stokes respiration, is common in patients with heart failure (HF) and associated with lower left ventricular ejection fraction (EF), increased arrhythmia burden, and increased mortality. Continuous positive airway pressure therapy improves short-term and long-term outcomes in HF patients. Adaptive servoventilation (ASV) therapy in patients with low-EF HF with predominant CSA is not recommended. Ongoing trials are evaluating whether ASV will have a role in SDB treatment. Phrenic nerve stimulation is an emerging treatment option that has shown promising outcomes. All HF patients should be screened for SDB.

Cheyne-stokes respiration in children with heart failure.

Cheyne-Stokes respiration (CSA-CSR) is a form of central sleep apnea characterized by alternating periods of hyperventilation and central apneas or hypopneas. CSA-CSR develops following a cardiac insult resulting in a compensatory increase in sympathetic activity, which in susceptible patients causes hyperventilation and destabilizes respiratory control. The physiological changes that occur in CSA-CSR include hyperventilation, a reduced blood gas buffering capacity, and circulatory delay. In adults, 25% to 50% of patients with heart failure are reported to have CSA-CSR. The development of CSA-CSR in this group of patients is considered a poor prognostic sign. The prevalence, progression, and treatment outcomes of CSA-CSR in children remain unclear with only 11 children being described in the literature. The lack of data is possibly not due to the paucity of children with severe heart failure and CSA-CSR but because they may be under-recognized, compounded by the absence of routine polysomnographic assessment of children with moderate to severe heart failure. Building on much broader experience in the diagnosis and management of CSA-CSR in adult sleep medicine and our limited experience in a pediatric quaternary center, this paper will discuss the prevalence of CSA-CSR, its' treatment options, outcomes in children, and the potential future direction for research in this understudied area of pediatric sleep medicine.

Disordered breathing in severe cerebral illness - Towards a conceptual framework.

Despite potentially life-threatening symptoms of disordered breathing in severe cerebral illness, there are no clear recommendations on diagnostic and therapeutic strategies for these patients. To identify types of breathing disorders observed in severely neurological comprised patients, to direct further research on classification, pathophysiology, diagnosis and treatment for disordered breathing in cerebral disease. Data including polygraphy, transcutaneous capnometry, blood gas analysis and radiological examinations of patients with severe cerebral illness and disordered breathing admitted to the neurological intensive care were analyzed. Patients (15) presented with acquired central hypoventilation syndrome (ACHS), central bradypnea, central tachypnea, obstructive, mixed and central apneas and hypopneas, Cheyne Stokes respiration, ataxic (Biot's) breathing, cluster breathing and respiration alternans. Severe cerebral illness may result in an ACHS and in a variety of disorders of the respiratory rhythm. Two of these, abrupt switches between breathing patterns and respiration alternans, suggest the existence of a rhythmogenic respiratory network. Polygraphy, transcutaneous capnometry, blood gas analysis and MRI are promising tools for diagnosis and research alike.

Cheyne-Stokes Respiration in a 17-Year-Old Boy Awaiting Heart Transplantation.

Cheyne-Stokes respiration is a pattern of alternating central apnea and hyperpnea. It is well described in adults with congestive heart failure, but not in children. We report the case of a 17-year-old boy whose systolic heart failure was complicated by Cheyne-Stokes respiration. He was given supportive therapy until heart transplant, after which his Cheyne-Stokes respiration clinically resolved. Clinicians should be aware of this uncommon condition in pediatric and adolescent patients who have advanced heart failure and irregular breathing.

A case of Cheyne-Stokes breathing emerging in a patient with atrial fibrillation and an implanted hypoglossal nerve stimulator.

Treatment emergent central sleep apnea (TECSA) can occur with positive airway pressure (PAP) therapy, mandibular advancement devices, and now recent cases with hypoglossal nerve stimulator (HNS) therapy during treatment for obstructive sleep apnea (OSA). There have been few published reports of Cheyne-Stokes breathing (CSB) emerging after implantation of an HNS. We present a case of a 76-year-old male with chronic atrial fibrillation and OSA who developed significant CSB after implantation of an HNS device. As popularity increases for alternative treatments of OSA, there should be close monitoring for emergence of CSB, especially in those who may have a propensity for high loop gain abnormalities contributing to central sleep apneas, such as patients with chronic atrial fibrillation. Further research is needed on CSA in patients with HNS implantation and atrial fibrillation, the prevalence of TECSA in the growing HNS therapy population, and the development of future management strategies. CITATION: Hong H, Oster J, Grover A, Ismail K. A case of Cheyne-Stokes breathing emerging in a patient with atrial fibrillation and an implanted hypoglossal nerve stimulator. J Clin Sleep Med. 2021;17(8):1731-1735.

Continuous positive airway pressure improves work of breathing in pediatric chronic heart failure.

BACKGROUND: Sleep disordered breathing (SDB) is common in adults with chronic heart failure (CHF), but its prevalence in children remains unclear. Continuous positive airway pressure (CPAP) is the treatment of SDB but deleterious hemodynamic effects have been reported. METHODS: We prospectively analyzed SDB in children with CHF and the effect of CPAP on work of breathing (WOB) and cardiac index (CI). Children aged 6 months to 18 years old with CHF due to: 1) dilated cardiomyopathy (DM) with an ejection fraction < 45%, 2) functional single ventricle (SV) or 3) aortic or mitral valve disease awaiting surgery (VD) were eligible for the study. A polysomnography (PSG), measurement of WOB and CI during spontaneous breathing (SB) and CPAP (6, 8 and 10 cmH2O) were performed. RESULTS: Thirty patients with mean age of 6.4 ± 5 years were included (16 DM 16, 10 SV, 4 LV). Twenty (73%) patients had a normal sleep efficiency. Median apnoeas hypopnea index (IAH) was within normal range at 1.6 events/h (0, 14) events/hour. Only one patient had central sleep apnoeas, none had Cheyne-Stokes respiration, and 3 patients had an obstructive AHI between 5 and 10 events/hour. Optimal CPAP level decreased WOB (p = 0.05) and respiratory rate (p = 0.01). CONCLUSIONS: Severe SDB was uncommon in children with CHF. However, CPAP may be beneficial by decreasing WOB and respiratory rate without deleterious effects on CI.

Novel phrenic nerve stimulator treats Cheyne-Stokes respiration: polysomnographic insights.

None: A symptomatic patient with atrial fibrillation and Cheyne-Stokes respiration (CSR) was implanted with a transvenous phrenic nerve stimulation (TPNS) device-the remede System-that is indicated for adult patients with moderate to severe central sleep apnea. Sleep recordings demonstrated that TPNS eliminated periodic breathing by activating the diaphragm and stabilizing respiratory patterns. These recordings of preprogrammed periods on versus off TPNS illustrate prompt (1) stabilization of tidal airflow, respiratory effort, and oxygenation as stimulation amplitude increased stepwise and (2) recurrence of CSR immediately after TPNS deactivated. Despite differences in respiratory patterns, minute ventilation was comparable during periods on and off TPNS. These findings suggest that diaphragmatic pacing entrains ventilation without disrupting sleep, accounting for observed improvements in periodic breathing, gas exchange, sleep architecture, and quality of life. Effective means to relieve CSR could potentially mitigate nocturnal cardiovascular stress and disease progression.

Bioprofiles and mechanistic pathways associated with Cheyne-Stokes respiration: insights from the SERVE-HF trial.

INTRODUCTION: The SERVE-HF trial included patients with heart failure and reduced ejection fraction (HFrEF) with sleep-disordered breathing, randomly assigned to treatment with Adaptive-Servo Ventilation (ASV) or control. The primary outcome was the first event of death from any cause, lifesaving cardiovascular intervention, or unplanned hospitalization for worsening heart failure. A subgroup analysis of the SERVE-HF trial suggested that patients with Cheyne-Stokes respiration (CSR) < 20% (low CSR) experienced a beneficial effect from ASV, whereas in patients with CSR ≥ 20% ASV might have been harmful. Identifying the proteomic signatures and the underlying mechanistic pathways expressed in patients with CSR could help generating hypothesis for future research. METHODS: Using a large set of circulating protein-biomarkers (n = 276, available in 749 patients; 57% of the SERVE-HF population) we sought to investigate the proteins associated with CSR and to study the underlying mechanisms that these circulating proteins might represent. RESULTS: The mean age was 69 ± 10 years and > 90% were male. Patients with CSR < 20% (n = 139) had less apnoea-hypopnea index (AHI) events per hour and less oxygen desaturation. Patients with CSR < 20% might have experienced a beneficial effect of ASV treatment (primary outcome HR [95% CI] = 0.55 [0.34-0.88]; p = 0.012), whereas those with CSR ≥ 20% might have experienced a detrimental effect of ASV treatment (primary outcome HR [95% CI] = 1.39 [1.09-1.76]; p = 0.008); p for interaction = 0.001. Of the 276 studied biomarkers, 8 were associated with CSR (after adjustment and with a FDR1%-corrected p value). For example, higher PAR-1 and ITGB2 levels were associated with higher odds of having CSR < 20%, whereas higher LOX-1 levels were associated with higher odds of CSR ≥ 20%. Signalling, metabolic, haemostatic and immunologic pathways underlie the expression of these biomarkers. CONCLUSION: We identified proteomic signatures that may represent underlying mechanistic pathways associated with patterns of CSR in HFrEF. These hypothesis-generating findings require further investigation towards better understanding of CSR in HFrEF. SUMMARY OF THE FINDINGS: PAR-1 proteinase-activated receptor 1, ADM adrenomedullin, HSP-27 heat shock protein-27, ITGB2 integrin beta 2, GLO1 glyoxalase 1, ENRAGE/S100A12 S100 calcium-binding protein A12, LOX-1 lectin-like LDL receptor 1, ADAM-TS13 disintegrin and metalloproteinase with a thrombospondin type 1 motif, member13 also known as von Willebrand factor-cleaving protease.

Effect of Treatment of Central Sleep Apnea/Cheyne-Stokes Respiration on Left Ventricular Ejection Fraction in Heart Failure: A Network Meta-Analysis.

STUDY OBJECTIVES: Patients who have experienced heart failure with central sleep apnea/Cheyne-Stokes respiration (CSA/CSR) have an impaired prognosis. Continuous positive airway pressure (CPAP) and adaptive servoventilation (ASV) as well as nocturnal oxygen (O2) are proposed treatment modalities of CSA/CSR. The goal of the study is to assess whether and how different treatments of CSA/CSR affect cardiac function. METHODS: Databases were searched up to December 2017 for randomized controlled trials (RCTs) comparing the effect of any combination of CPAP, ASV, O2 or an inactive control on left ventricular ejection fraction (LVEF) in patients with heart failure and CSA/CSR. A systematic review and network meta-analysis using multivariate random-effects meta-regression were performed. RESULTS: Twenty-four RCTs (1,289 patients) were included in the systematic review and data of 16 RCTs (951 patients; apnea-hypopnea-index 38 ± 3/h, LVEF 29 ± 3%) could be pooled in a network meta-analysis. Compared to an inactive control, both CPAP and ASV significantly improved LVEF by 4.4% (95% confidence interval 0.3-8.5%, P = 0.036) and 3.8% (95% confidence interval 0.6-7.0%, P = 0.025), respectively, whereas O2 had no effect on LVEF (P = 0.35). There was no difference in treatment effects on LVEF between CPAP and ASV (P = 0.76). The treatment effect of positive pressure ventilation was larger when baseline LVEF was lower in systolic heart failure. CONCLUSIONS: CPAP and ASV are effective in improving LVEF in patients with heart failure and CSA/CSR to a clinically relevant amount, whereas nocturnal O2 is not. There is no difference between CPAP and ASV in the comparative beneficial effect on cardiac function.

Ventilation Parameters under Adaptive Servo Ventilation: A Comparison on Behalf of CSA-Pattern, BNP/NT-pro-BNP, and Ejection Fraction.

BACKGROUND: The SERVE-HF study has raised questions concerning the higher mortality under adaptive servoventilation. The ventilatory mode was discussed as a possible aggravating factor. OBJECTIVES: We wondered if the data recorded by the adaptive servo-ventilation (ASV)-devices in heart failure patients with CSA-CSR ± OSA are different in terms of respiratory parameters and therapeutic pressures compared to patients with CPAP-resistant/emergent-CSA with normal BNP/NT-pro-BNP. METHODS: Patients were included, if ASV had normalized respiratory disturbance index in the first night of application and after at least 6 weeks. ASV-device data were analyzed in terms of respiratory rate (RR), min ventilation (MV), endexpiratory (EEP), peak inspiratory pressure (Ppeak) and median pressure. RESULTS: Compared to CPAP-resistant/emergent-CSA with normal BNP/NT-pro-BNP (n = 25), CSA-CSR- (n = 13) CSA-CSR+OSA-patients (n = 32) with elevated BNP/NT-pro-BNP had higher RR (p < 0.01) in the first night of ASV therapy and during follow-up (15.3 ± 1.3 vs. 17.3 ± 2.4/min) with similar MV (6.5 ± 1.3 vs. 6.6 ± 1.3 L), resulting in significantly lower tidal volumes. EEP (5.6 ± 1.1 vs. 5.5 ± 1.1 hPa), Pmedian and Ppeak (9.8 ± 1.5 vs. 9.7 ± 1.2 hPa) were comparable. Ventilatory parameters were not different between LVEF < 40, 40-49, and ≥50%, neither within the whole group nor the group of CSA-CSR ± OSA and heart failure. CONCLUSION: Patients with heart failure and CSA-CSR ± OSA have higher RRs but similar MV under ASV-therapy than patients with CSA and normal BNP. This indicates higher dead space ventilation. EF was not found to have an influence on the ventilatory parameters.

Central Sleep Apnea with Cheyne-Stokes Breathing in Heart Failure - From Research to Clinical Practice and Beyond.

Characterized by periodic crescendo-decrescendo pattern of breathing alternating with central apneas, Central sleep apnea (CSA) with Cheyne-Stokes Breathing represents a highly prevalent, yet underdiagnosed comorbidity in chronic heart failure (CHF). A diverse body of evidence demonstrates increased morbidity and mortality in the presence of CSB. CSB has been described in both CHF patients with preserved and reduced ejection fraction, regardless of drug treatment. Risk factors for CSB are older age, male gender, high BMI, atrial fibrillation and hypocapnia.The pathophysiology of CSB has been explained by the loop gain theory, where a controller (the respiratory center) and a plant (the lungs) are operating in a reciprocal relationship (negative feedback) to regulate a key parameter (partial pressure of carbon dioxide (pCO2)). The temporal interaction between these elements is dependent on the circulatory delay. Increased chemosensitivity/chemoresponsiveness of the respiratory center and/or augmented ascending non- CO2 stimuli from the C-fibers in the lungs (interstitial pulmonary edema), overly efficient ventilation when breathing at low volumes and prolonged circulation time are involved. An alternative hypothesis of CSB being an adaptive response of the failing heart has its merits as well. The clinical manifestation of CSB is usually poor, lacking striking symptoms and complaints. Witnessed apneas and snoring are infrequently reported by the sleep partner. Sometimes patients may report poor sleep quality with frequent awakenings, paroxysmal nocturnal dyspnea and frequent urination at night. Standard instrumental and laboratory studies, performed in CHF patients, may present clues to the presence of CSB. Concentric remodeling of the left ventricle and dilated left atrium (echocardiography), high BNP and C-reactive protein levels, increased ventilation-carbon dioxide output (VEVCO2) and lower end-tidal CO2 (cardiopulmonary exercise testing), reduced diffusion capacity (pulmonary function testing) and hypocapnia (blood-gas analysis) may indicate the presence of CSB.CSB and cardiovascular disease are probably linked through bidirectional causality. Cyclic variations in heart rate, blood pressure, respiratory volume, partial pressure of arterial oxygen (pO2) and pCO2 lead to sympathetic-adrenal activation. The latter worsens ventricular energetism and survival of cardiomyocytes and exerts antiarhythmogenic effects. It causes cardiac remodeling, potentiating the progression and the lethal outcome in CHF patients. Several treatment modalities have been proposed in CSB. The most commonly used are continuous positive airway pressure (CPAP), adaptive servoventilation (ASV) and nocturnal home oxygen therapy (HOT). Novel therapies like nocturnal supplemental CO2 and phrenic nerve stimulation are being tested recently. The current treatment recommendations (by the American Academy of Sleep Medicine) are for CPAP and HOT as standard therapies, while ASV is an option only in patients with EF > 45%. BPAP (bilevel device) remains an option only when there is no adequate response to previous modes of treatment. Acetazolamide and theophylline are options only after failing the above modalities and if accompanied by a close follow-up.