Chronic Opioid Use and Central Sleep Apnea, Where Are We Now and Where To Go? A State of the Art Review.

Opioids are commonly used for pain management, perioperative procedures, and addiction treatment. There is a current opioid epidemic in North America that is paralleled by a marked increase in related deaths. Since 2000, chronic opioid users have been recognized to have significant central sleep apnea (CSA). After heart failure-related Cheyne-Stokes breathing (CSB), opioid-induced CSA is now the second most commonly seen CSA. It occurs in around 24% of chronic opioid users, typically after opioids have been used for more than 2 months, and usually corresponds in magnitude to opioid dose/plasma concentration. Opioid-induced CSA events often mix with episodes of ataxic breathing. The pathophysiology of opioid-induced CSA is based on dysfunction in respiratory rhythm generation and ventilatory chemoreflexes. Opioids have a paradoxical effect on different brain regions, which result in irregular respiratory rhythm. Regarding ventilatory chemoreflexes, chronic opioid use induces hypoxia that appears to stimulate an augmented hypoxic ventilatory response (high loop gain) and cause a narrow CO2 reserve, a combination that promotes respiratory instability. To date, no direct evidence has shown any major clinical consequence from CSA in chronic opioid users. A line of evidence suggested increased morbidity and mortality in overall chronic opioid users. CSA in chronic opioid users is likely to be a compensatory mechanism to avoid opioid injury and is potentially beneficial. The current treatments of CSA in chronic opioid users mainly focus on continuous positive airway pressure (CPAP) and adaptive servo-ventilation (ASV) or adding oxygen. ASV is more effective in reducing CSA events than CPAP. However, a recent ASV trial suggested an increased all-cause and cardiovascular mortality with the removal of CSA/CSB in cardiac failure patients. A major reason could be counteracting of a compensatory mechanism. No similar trial has been conducted for chronic opioid-related CSA. Future studies should focus on (1) investigating the phenotypes and genotypes of opioid-induced CSA that may have different clinical outcomes; (2) determining if CSA in chronic opioid users is beneficial or detrimental; and (3) assessing clinical consequences on different treatment options on opioid-induced CSA.

Central sleep apnoea and periodic breathing in heart failure: prognostic significance and treatment options.

Central sleep apnoea (CSA) including periodic breathing is prevalent in more than one-third of patients with heart failure and is highly and independently associated with poor outcomes. Optimal treatment is still debated and well-conducted studies regarding efficacy and impact on outcomes of available treatment options are limited, particularly in cardiac failure with preserved ejection fraction. While continuous positive airway pressure and oxygen reduce breathing disturbances by 50%, adaptive servoventilation (ASV) normalises breathing disturbances by to controlling the underlying mechanism of CSA. Results are contradictory regarding impact of ASV on hard outcomes. Cohorts and registry studies show survival improvement under ASV, while secondary analyses of the large SERVE-HF randomised trial showed an excess mortality in cardiac failure with reduced ejection fraction. The current priority is to understand which phenotypes of cardiac failure patients may benefit from treatment guiding individualised and personalised management.

Effects of Adaptive Servoventilation Therapy for Central Sleep Apnea on Health Care Utilization and Mortality: A Population-Based Study.

STUDY OBJECTIVES: Adaptive servoventilation (ASV) is the suggested treatment for many forms of central sleep apnea (CSA). We aimed to evaluate the impact of treating CSA with ASV on health care utilization. METHODS: In this population-based study using the Rochester Epidemiology Project database, we identified patients over a 9-year period who were diagnosed with CSA (n = 1,237), commenced ASV therapy, and had ≥ 1 month of clinical data before and after ASV initiation. The rates of hospitalizations, emergency department visits (EDV), outpatient visits (OPV) and medications prescribed per year (mean ± standard deviation) in the 2 years pre-ASV and post-ASV initiation were compared. RESULTS: We found 309 patients (68.0 ± 14.6 years, 80.3% male, apnea-hypopnea index 41.6 ± 26.5 events/h, 78% with cardiovascular comorbidities, 34% with heart failure) who met inclusion criteria; 65% used ASV ≥ 4 h/night on ≥ 70% nights in their first month. The overall 2-year mortality rate was 9.4% and CSA secondary to cardiac cause was a significant risk factor for mortality (hazard ratio 1.81, 95% CI 1.09-3.01, P = .02). Comparing pre-ASV and post-ASV initiation, there was no change in the rate of hospitalization (0.72 ± 1.63 versus 0.79 ± 1.44, P = .46), EDV (1.19 ± 2.18 versus 1.26 ± 2.08, P = .54), OPV (31.59 ± 112.42 versus 13.60 ± 17.36, P = .22), or number of prescribed medications (6.68 ± 2.0 versus 5.31 ± 5.86, P = .06). No differences in these outcomes emerged after accounting for adherence to ASV, CSA subtype and comorbidities via multiple regression analysis (all P > .05). CONCLUSIONS: Our cohort of patients with CSA was quite ill and the use of ASV was not associated with a change in health care utilization.

Sleep-Disordered Breathing in Heart Failure　- A Therapeutic Dilemma.

Sleep-disordered breathing (SDB) occurs in approximately 50% of patients with reduced left ventricular ejection fraction receiving contemporary heart failure (HF) therapies. Obstructive (OSA) and central sleep apneas (CSA) interrupt breathing by different mechanisms but impose qualitatively similar autonomic, chemical, mechanical, and inflammatory burdens on the heart and circulation. Because contemporary evidence-based drug and device HF therapies have little or no mitigating effect on the acute or long-term consequences of such stimuli, there is a sound mechanistic rationale for targeting SDB to reduce cardiovascular event rates and prolong life. However, the promise of observational studies and randomized trials of small size and duration describing a beneficial effect of treating SDB in HF via positive airway pressure was not realized in 2 recent randomized outcome-driven trials: SAVE, which evaluated the cardiovascular effect of treating OSA in a cohort without HF, and SERVE-HF, which reported the results of a strategy of random allocation of minute-ventilation-triggered adaptive servo-ventilation (ASV) for HF patients with CSA. Whether effective treatment of either OSA or CSA improves the HF trajectory by reducing cardiovascular morbidity or mortality has yet to be definitively established. ADVENT-HF, designed to determine the effect of treating both CSA and non-sleepy OSA HF patients with a peak-airflow triggered ASV algorithm, could resolve this present clinical equipoise concerning the treatment of SDB.

[Guidelines in Practice: The New S3 Guideline "Sleeping Disorders - Sleep-Related Abnormal Breathing"]. / Leitlinien in der Praxis: Die neue S3-Leitlinie "Nicht erholsamer Schlaf/Schlafstörungen" ­ Kapitel "Schlafbezogene Atmungsstörungen".

Sleep related breathing disorders include central sleep apnea (CSA), obstructive sleep apnea (OSA), sleep-related hypoventilation, and sleep-related hypoxia. These disorders are frequent and growing in clinical relevance. The related chapter of the S3 guideline "Non-restorative sleep/Sleep disorders", published by the German Sleep Society (DGSM), has recently been updated in November 2016. Epidemiology, diagnostics, therapeutic procedures, and classification of sleep related disorders have been revised. Concerning epidemiology, a considerably higher mortality rate among pregnant women with OSA has been emphasized. With regards to diagnostics, the authors point out that respiratory polygraphy may be sufficient in diagnosing OSA, if a typical clinical condition is given. For CSA, recommendations were changed to diagnose CSA with low apnea rates present. Significant changes for treating CSA in patients with left ventricular dysfunction have been introduced. In addition, there is now to be differentiated between sleep-related hypoventilation and sleep-related hypoxaemia. Obesity hypoventilation syndrome is discussed in more detail. This article sums up and comments on the published changes.

Mechanisms underlying increased mortality risk in patients with heart failure and reduced ejection fraction randomly assigned to adaptive servoventilation in the SERVE-HF study: results of a secondary multistate modelling analysis.

BACKGROUND: A large randomised treatment trial (SERVE-HF) showed that treatment of central sleep apnoea with adaptive servoventilation in patients with heart failure and reduced ejection fraction (HFREF) increased mortality, although the analysis of the composite primary endpoint (time to first event of death from any cause, life-saving cardiovascular intervention, or unplanned hospital admission for worsening heart failure) was neutral. This secondary multistate modelling analysis of SERVE-HF data investigated associations between adaptive servoventilation and individual components of the primary endpoint to try to better understand the mechanisms underlying the observed increased mortality. METHODS: In SERVE-HF, participants were randomly assigned to receive either optimum medical treatment for heart failure alone (control group), or in combination with adaptive servoventilation. We analysed individual components of the primary SERVE-HF endpoint separately in a multistate model, with and without three covariates suggested for effect modification (implantable cardioverter defibrillator at baseline, left ventricular ejection fraction [LVEF], and proportion of Cheyne-Stokes Respiration [CSR]). The SERVE-HF study is registered with ClinicalTrials.gov, number NCT00733343. FINDINGS: Univariate analysis showed an increased risk of both cardiovascular death without previous hospital admission (hazard ratio [HR] 2·59, 95% CI 1·54-4·37, p<0·001) and cardiovascular death after a life-saving event (1·57, 1·01-2·44, p=0·045) in the group receiving adaptive servoventilation versus the control group. Adjusted analysis showed that the increased risk attributed to adaptive servoventilation of cardiovascular death without previous hospital admission for worsening heart failure varied with LVEF and that the risk attributed to adaptive servoventilation of hospital admission for worsening heart failure varied with LVEF and CSR. In patients with LVEF less than or equal to 30%, use of adaptive servoventilation markedly increased the risk of cardiovascular death without previous hospital admission (HR 5·21, 95% CI 2·11-12·89, p=0·026). INTERPRETATION: Adaptive servoventilation is associated with an increased risk of cardiovascular death in patients with heart failure and reduced ejection fraction (LVEF ≤45%) treated for predominant central sleep apnoea. This multistate modelling analysis shows that this risk is increased for cardiovascular death in patients not previously admitted to hospital, presumably due to sudden death, and in patients with poor left ventricular function. FUNDING: ResMed.

Is servoventilation in central sleep apnea syndrom still working?.

Last black box on adaptive servoventilation in central apnoea syndrome generate many connective problems concerning the alternative therapies. The authors are starting from two recent french articles on this same subject and are trying to see what is missing and what we have to do.

Nocturnal hypoxaemia is associated with increased mortality in stable heart failure patients.

AIM: This study investigated the prognostic value of sleep-disordered breathing (SDB) in a large cohort of patients with heart failure with reduced left ventricular function (HF-REF), with focus on the role of nocturnal hypoxaemia. METHODS: This single-centre prospective cohort study enrolled patients with chronic stable HF-REF (NYHA ≥II) receiving guideline-based treatment. Unattended in-hospital polygraphy was performed to determine the apnoea-hypopnoea index (AHI). Pulse oximetry was used to determine hypoxaemic burden [time with oxygen saturation <90% (T90)], and all-cause mortality was recorded. RESULTS: Complete data were available for 963 of 1249 patients. At baseline, 58% of patients had moderate-to-severe SDB. The median follow-up was 7.35 years; 480 of 963 (49.8%) patients died. Mortality rate (per 100 person-years) was 8.1 [95% confidence interval (CI) 7.0-9.4] in patients with no or mild SDB, but 12.2 (95% CI 10.9-13.7) in moderate-to-severe SDB. Apnoea-hypopnoea index was significantly associated with time to death from any cause in a simple Cox model [hazard ratio (HR) 1.011, P < 0.001], but was no longer significant after adjustment for confounding factors (HR 1.005, P = 0.085). T90 was significantly (P < 0.001) associated with time to death from any cause even after adjustment for confounding factors. The risk of death increased by 16.1% (95% CI 8.6-24.2) per hour of T90. Five-year survival probabilities for patients in T90 quartiles 1, 2, 3, and 4 were 70, 63, 60, and 50%, respectively. CONCLUSION: Hypoxaemic burden was a robust and independent predictor of all-cause mortality in chronic stable HF-REF patients. Whether or not targeting nocturnal hypoxaemia is associated with beneficial effects on mortality in HF-REF patients remains to be determined.

Prognostic impact of central sleep apnea in patients with heart failure.

BACKGROUND: Central sleep apnea (CSA) is common in patients with heart failure (HF). Earlier studies investigating the influence of CSA on mortality in HF patients, however, have yielded contradictory results. METHODS AND RESULTS: In a prospective study involving 267 patients with left ventricular (LV) ejection fractions ≤50%, we performed polysomnography and compared heart transplant-free survival rates between patients with no or mild CSA (apnea-hypopnea index [AHI] ≤15/h) and those with moderate CSA (AHI 15.1-30/h) or severe CSA (AHI >30/h). During 43 ± 18 months' mean follow-up, 67 patients (25%) died and 4 patients (1%) underwent heart transplantation. Multivariate Cox analysis identified age, male sex, chronic kidney disease, and decreased LV ejection fraction, but not moderate CSA or severe CSA, as predictors of transplant-free survival. CONCLUSIONS: In patients with stable HF, moderate CSA as well as severe CSA do not appear to predict transplant-free survival independently from confounding factors.

[Cheyne-Stokes respiration in patients with chronic heart failure: only a diagnostic marker or also a cardiovascular risk factor?]. / Cheyne-Stokes-Atmung bei Patienten mit chronischer Herzinsuffizienz: nur diagnostischer "Marker" oder auch kardialer Risikofaktor?

Sleep disordered breathing with predominant obstructive or central apnea is an under-recognized but highly prevalent comorbidity in patients with chronic heart failure. As the severity of heart failure increases the prevalence of central sleep apnea (CSA) and Cheyne-Stokes respiration (CSR) is also much more frequent. Cheyne-Stokes respiration is characterized by alternating periods of crescendo and decrescendo respiration followed by central apnea. Present data indicate that CSA-CSR is not only a compensatory response to severe heart failure but also a predictor of worse prognosis. However the results on long-term mortality are not consistent. The prognostic importance of night- and daytime CSR has to be further elucidated. Increased sympathetic nervous activity has been proposed to play a mayor role concerning progression and outcome of chronic heart failure by CSA-CSR.

A novel therapeutic approach for the treatment of central sleep apnea: The remede® system.

Central sleep apnea (CSA) occurs primarily in cardiovascular patients and is associated with high morbidity and mortality. The disorder often is unrecognized due to the overlap of symptoms with those of the underlying cardiac disease. CSA can be easily diagnosed with a sleep study. Following optimization of all co-morbidities, the therapeutic approach available currently focuses on mask-based therapies which suffer from poor patient adherence. A new therapy, the remede® System, has been developed; it utilizes a transvenous, fully implantable system providing phrenic nerve stimulation intended to restore a more normal breathing pattern. The therapy demonstrated promising results based on an initial chronic study and a randomized trial is underway to further evaluate safety and efficacy of this novel system in patients with CSA.

Sleep-disordered breathing in patients with implantable cardioverter-defibrillator.

AIMS: To assess the prognostic significance of screening for sleep-disordered breathing in patients with implantable cardioverter-defibrillator (ICD) with regard to appropriate ICD therapy and total mortality. METHODS AND RESULTS: Overnight sleep studies were performed in 204 ICD recipients not known to have sleep apnoea and with no history of daytime sleepiness. Sleep-disordered breathing was diagnosed in the presence of an apnoea-hypopnea index of five or more events per hour. Seventy patients (34%) had no sleep apnoea, 105 patients (51%) had central sleep apnoea, and 29 patients (14%) had obstructive sleep apnoea. During 38 ± 26 months follow-up, 80 patients (39%) received appropriate ICD therapy for ventricular tachycardia (VT) or ventricular fibrillation (VF), and 54 patients (26%) died. On multivariate Cox regression analysis, age, left ventricular (LV) end-diastolic diameter, secondary prevention ICD indication, use of diuretics, and absence of aldosterone antagonist therapy but not sleep apnoea were associated with appropriate ICD therapy for VT or VF. In addition, multivariate Cox analysis identified age and LV ejection fraction but not sleep apnoea as predictors of total mortality. CONCLUSION: Undiagnosed sleep-disordered breathing is common in ICD recipients. The presence and severity of previously unknown sleep apnoea in ICD recipients, however, does not appear to be an independent predictor of appropriate ICD therapy or morality during follow-up.

Clinical characteristics and mortality risk in relation to obstructive and central sleep apnoea in community-dwelling elderly individuals: a 7-year follow-up.

BACKGROUND: little is known about demographic and clinical characteristics associated with sleep-disordered breathing (SDB) and obstructive sleep apnoea (OSA) or central sleep apnoea (CSA) in community-dwelling elderly. We also examined these (OSA and CSA) associations to all-cause and cardiovascular (CV) mortality. METHODS: a total of 331 community-dwelling elderly aged 71-87 years underwent a clinical examination and one-night polygraphic recordings in their homes. Mortality data were collected after seven years. RESULTS: a total of 55% had SDB, 38% had OSA and 17% had CSA. Compared with those with no SDB and OSA, more participants with CSA had a left ventricular ejection fraction <50% (LVEF <50%) ischaemic heart disease (IHD) and transient ischaemic attack (TIA)/stroke. There was no difference in the rate of IHD and TIA/stroke between OSA and no SDB, but more LVEF <50% was found in those with OSA. CSA significantly increased the risk for all-cause (P=0.002) and CV mortality (P=0.018) by more than two times. After adjustments for CV disease, diabetes and the biomarker NT-pro-brain natriuretic peptide CSA associations to all-cause mortality and CV mortality lost significance. CONCLUSION: OSA, in persons >75 years does not appear to be associated with cardiovascular disease (CVD) disease or mortality, whereas CSA might be a pathological marker of CVD and impaired systolic function associated with higher mortality.

Impact of untreated sleep apnea on prognosis of patients with congestive heart failure.

128 congestive heart failure (CHF) patients with a median age of 55 years and median left ventricular ejection fraction of 35.4% were followed up for a median period of 35 months. 23 (18%) had no sleep apnea (CHF-N), 55 (43%) had obstructive sleep apnea (CHF-OSA), and 50 (39%) had central sleep apnea (CHF-CSA). At the end of follow-up, mortality was greater in the CHF-CSA group than in the CHF-N group (18.2 vs 6.7/100 person-years, p=0.017). However, after adjusting age and the New York Heart Association functional class central sleep apnea, obstructive sleep apnea, or the severity of sleep apnea are not predictors for survival in CHF. In addition, the percentages of combined events were not significantly different among three groups. Untreated sleep apnea has no independent impact on the prognosis of patients with CHF.

[Ondine syndrome or central congenital hypoventilation syndrome]. / Syndrome d'Ondine ou hypoventilation alvéolaire centrale congénitale. .

Congenital central hypoventilation syndrome (CCHS) is a rare disease due to a severely impaired central autonomic control of breathing and dysfunction of the autonomous nervous system. The incidence is estimated to be at 1 of 200,000 livebirths. A heterozygous mutation of PHOX-2B gene is found in 90% of the patients. Association with a Hirschsprung's disease is observed in 16% of the cases. Despite a high mortality rate and a lifelong dependence to mechanical ventilation, the long-term outcome of CCHS should be ultimately improved by multidisciplinary and coordinated follow-up of the patients.

The French Congenital Central Hypoventilation Syndrome Registry: general data, phenotype, and genotype.

OBJECTIVE: To analyze the main clinical features, genetic mutations, and outcomes of patients of the French Congenital Central Hypoventilation Syndrome (CCHS) Registry. DESIGN: A country-wide cohort established throughout a long-term multicenter effort. PATIENTS: Seventy French patients with CCHS (29 male patients and 41 female patients). METHODS: The following items were analyzed: the most important moments of the disease course; the main clinical characteristics; associated pathologic conditions; management; clinical outcome; and genetic mutations. RESULTS: An average of four new cases of CCHS per year was observed in the last 5 years. Thus, the incidence may be estimated to be 1 per 200,000 live births in France. The median age at diagnosis was 3.5 months (range, 0.5 to 15 months) before 1995 and < 2 weeks in the last 5 years (p = 0.01). CCHS occurred in isolation in 58 of 70 patients. In the remainder, it was associated with Hirschsprung disease (HSCR) [nine patients], Hirschsprung and neural crest tumor (two patients), and growth hormone deficiency (one patient). Among the 50 patients who lived beyond 1 year of age, all but one received nighttime ventilation, with 10 of them (20%) receiving it noninvasively. Three patients (6%) required daytime ventilatory support in addition to nighttime ventilation. The overall mortality rate was 38% (95% confidence interval [CI], 27 to 49%). The median age at death was 3 months (range, 0.4 months to 21 years). The 2-year mortality rate was greater in male patients than in female patients (p = 0.02; relative risk [RR], 2.71; 95% CI, 1.14 to 6.47) but was not affected by HSCR (p = 0.93; RR, 0.95; 95% CI, 0.28 to 3.2). The 43 patients who are currently alive (11 men; sex ratio, 0.4) have a mean age of 9 years (range, 2 months to 27 years). Among the 34 patients tested thus far, heterozygous mutations of the paired-like homeobox gene 2B (PHOX2B) gene were found in 31 patients (91%). CONCLUSION: Our four major findings are the extreme rarity of CCHS, the improved recognition over time, the lack of effect of HSCR on the mortality rate, and the high frequency of PHOX2B mutations.