Revisiting Hypopnea Classification and Emerging Neuromodulation Therapies in Central Sleep Apnea

Opioids are known to contribute to central sleep apnea (CSA), but the influence of nonopioid central nervous system active medications (CNSAMs) on CSA remains unclear. In light of the hypothesized impact of nonopioid CNSAMs on respiration, we examined the relationships between the use of opioids only, nonopioid CNSAMs alone, and their combination with CSA. Among all adults who underwent polysomnography testing at the University of Michigan's sleep laboratory between 2013 and 2018 (n = 10,606), we identified 212 CSA cases and randomly selected 300 controls. Participants were classified into four groups based on their medication use: opioids alone, nonopioid CNSAMs only, their combination, and a reference group, including those who did not use any of these medications. We defined CSA as a binary outcome and as a continuous variable using central apnea index data. Logistic and linear regression were used to examine associations between medication use, CSA diagnosis, and central apnea index. Study participants included 58% men, and mean age was 50 (± 14 standard deviation years. Nearly half of the study participants did not use opioids or nonopioid CNSAMs, 6% used opioids alone, 27% nonopioid CNSAMs alone, and 16% used a combination of these medications. In adjusted analyses, opioids-only users had a nearly twofold increase in CSA odds, whereas those who used a combination of opioids and nonopioid CNSAMs had fivefold higher odds of CSA relative to the reference group. In contrast, the use of nonopioid CNSAMs alone had protective associations with CSA. This report showed increased odds of CSA, particularly among patients with sleep complaints who were prescribed opioids in combination with nonopioid CNSAMs compared with those who did not use any of these medications.

To determine the rate of sleep-disordered breathing (SDB) in individuals with spinal cord injury (SCI) and its types (central sleep apnea and obstructive sleep apnea, and a comorbid central and obstructive sleep apnea and to assess the response to treatment using positive airway pressure (PAP) (defined as an apnea-hypopnea index (AHI) of less than 5 events/h on initial PAP titration) in individuals with SCI. Individuals with SCI who underwent a full night of diagnostic polysomnography from 2010-2024 to determine the type of SDB and its severity using the AHI and central apnea index. The inclusion criteria were individuals with chronic SCI at low cervical or thoracic (at C4-T6 levels) who are not mechanically ventilated or had tracheostomies. "Central sleep apnea" is diagnosed with an AHI of 5+ events/h and a central apnea index of at least 50% of the AHI. "Obstructive sleep apnea only" is identified by an AHI of 5+ events/h and a central apnea index of less than 5 events/h. Comorbid central and obstructive sleep apnea is characterized by an AHI of 5+ events/h, with a central apnea index over 5 events/h but under 50% of the total AHI. The positive response to PAP therapy was based on the AHI level of less than 5 events/h after initiating PAP treatment and based on remote monitoring data. Among the 81 individuals who met the inclusion criteria, 12 patients (15%) were diagnosed with comorbid central and obstructive sleep apnea, 4 patients (5%) presented with central sleep apnea only, 56 patients (69%) had obstructive sleep apnea, and 8 patients (10%) exhibited no SDB. In a subset of participants (n = 51) hypopneas were classified as obstructive or central events based on American Academy of Sleep Medicine definition and revealed that approximately one-third (32%) had central or comorbid central and obstructive sleep apnea, 63% had obstructive sleep apnea, and 6% did not have SDB on polysomnography. A total of 35 (47%) individuals diagnosed with SDB underwent PAP titration and were prescribed PAP. Twenty (27%) individuals received PAP treatment, and only 17 (23%) continued their use for the initial 3 months. Only 11 patients (15%) demonstrated responsiveness to PAP on day 90 (AHI < 5 events/h during therapy). SDB is extremely common in individuals with SCI. The efficacy of PAP therapy is suboptimal, and adherence rates decline significantly over time. Sankari A, Aldwaikat A, Habra M, etal. Sleep apnea in individuals with spinal cord injury. J Clin Sleep Med. 2025;21(9):1529-1537.

Central sleep apnea (CSA) may occasionally occur in patients with obstructive sleep apnea during titration with a continuous positive airway pressure (CPAP) device. To determine the prevalence and the natural history of CPAP-emergent CSA. This is a retrospective study of 1286 patients with a diagnosis of OSAwho underwent titration with a positive airway device during a 1-year period. Patients were seen in consultation and underwent full-night attended polysomnography followed by full-night attended CPAP titration. Four weeks after CPAP therapy, patients returned to the clinic for follow-up, and objective adherence to CPAP was recorded. In patients who had CSA on CPAP, a second full-night attended CPAP titration was recommended. Eighty-four of the 1286 patients developed a central apnea index (CAI) of 5 or greater per hour while on CPAP. The incidence of CSA varied from 3% to 10% monthly, with an overall incidence of 6.5%. Forty-two of the 84 patients returned for a second CPAP titration. In 33 patients, CSA was eliminated. In each of the remaining 9 patients, the CAI remained at 5 or greater per hour, with an average of 13 per hour. These patients characteristically had the most severe OSA, and 5 had a CAI of 5 or more per hour at baseline. Two of the 9 patients were on opioids In this large retrospective study of 1286 patients with a diagnosis of OSA, 6.5% had CPAP-emergent or persistent CSA. However, CPAP-emergent CSA was generally transitory and was eliminated within 8 weeks after CPAP therapy. The prevalence of CPAP-persistent CSA was about 1.5%. Severity of OSA, a CAI of 5 or greater per hour, and use of opioids were potential risk factors.

Central sleep apnea (CSA) syndromes (CSAS) and sleep-related hypoventilation disorders encompass a group of sleep-related breathing disorders with diverse pathophysiology, ranging from instability of the respiratory metabolic control system to impaired lung function or chest wall mechanics. Based upon their effect on arterial CO2 concentration, these diseases can be divided into two groups: those with “hypocapnic–eucapnic CSA” and those with “hypercapnic CSA.” Even though the clinical presentation and sleep-related complaints may overlap, characteristic patterns in the polysomnographic airflow, overnight oximetry trace, and pulmonary function test can differentiate them further. The current evidence supports the treatment of CSA with modified methods of delivering positive airway pressure. Otherwise, limited evidence is available to support pharmacological intervention. Practical application of gas therapy is limited to nocturnal oxygen supplementation for the treatment of CSAS related to congestive heart failure (CHF). Further research is needed to expand our knowledge of CSAS pathophysiology and to develop novel therapeutic strategies.

Heterogeneity of Response to Constant Positive Pressure in Patients With Heart Failure and Coexisting Central and Obstructive Sleep Apnea: Response

A New Straw in the Genesis of Cheyne-Stokes Respiration

PurposeWhen navigating the landscape of obstructive sleep apnea (OSA), central sleep apnea (CSA) and intersection of the two diseases (co-existing CSA-OSA), there are significant knowledge gaps. Data are scarce regarding the respective prevalence and differences in clinical presentation of the three conditions. One major issue for characterization of the prevalence of the different sleep apnea entities is the scoring of central versus obstructive hypopneas which is not included in the routine practice of many sleep laboratories. MethodWe prospectively assessed multidomain symptoms and collected data on comorbidities, medications and treatment indications in a large monocentric real-life dataset (n > 2400) of patients referred for suspicion of sleep apnea. We have systematically distinguished central versus obstructive hypopneas to define OSA, CSA and co-existing CSA-OSA. ResultsWhen CSA was defined by the proportion of central apneas (and hypopneas were considered obstructive by default), the prevalence of CSA was 4.59 % (co-existing CSA-OSA: 11.03 %, and OSA: 84.37 %). When the distinction between obstructive and central hypopneas was used to classify the sleep disordered breathing, the prevalence of CSA was fourfold higher at 19.69 % (co-existing: 19.16 %, OSA: 61.16 %). The burden of cardiovascular and metabolic comorbidities was the highest in the CSA and co-existing sleep apnea subgroups. The three sleep apnea groups exhibited different constellations of symptoms but most of the patients with CSA, co-existing and OSA were symptomatic after comprehensive evaluation. The CSA group exhibited the most severe disturbances in sleep architecture on polysomnography. Therapeutic indications differed depending on the subtype of respiratory events. ConclusionOur findings imply that not differentiating between central and obstructive hypopneas will underestimate the severity of central sleep disordered breathing abnormalities that mislead therapeutic decisions and might limit improvements in quality of life and sleepiness that are expected in appropriately treated patients with CSA.

Multimodality Therapy for Sleep Apnea Syndromes

Sleep is generally considered to be a protected period, when the cardiovascular system benefits from the restorative influences of the sleeping brain. However, the dynamics of cardiovascular control during sleep can tax the capacity of the diseased coronary circulation and myocardium with surges in sleep-state–related autonomic activity and disruptions in airway function and central nervous system regulation. In this regard, sleep may constitute an autonomic stress test for the heart. The scope of sleep-related risk for atrial and ventricular arrhythmias is substantial. The major subgroups susceptible to adverse influences of surges in autonomic activity during sleep are those with ischemic heart disease, heart failure, and channelopathies (Table).1 It is significant that 20% of myocardial infarctions and 15% of sudden deaths occur at night in the United States.2 Most atrial arrhythmias in patients younger than 61 years of age have nocturnal onset.3 The young are not immune to risk, as sudden infant death syndrome (SIDS) claims 2500 lives in the United States annually.4 Cardiovascular risk is compounded by comorbid factors, most notably apnea, which affects an estimated 4% to 9% of the general population5 and is considerably more prevalent among obese individuals.6 The more common form is obstructive sleep apnea (OSA), with partial or complete collapse of the pharynx. Half of heart failure patients experience either OSA or central sleep apnea (CSA) with central nervous system–mediated periodic breathing, commonly referred to as Cheyne-Stokes respiration. Such cardiorespiratory disturbances profoundly alter autonomic nervous system activity and increase risk of arrhythmia, hypertension, and myocardial infarction. View this table: Table. Patient Groups at Potentially Increased Risk for Nocturnal Cardiac Events It is surprising, as recently underscored by Malhotra and Loscalzo,7 that the significance of cardiovascular risk during sleep may not be duly recognized within the cardiology community. The reasons are …

Prevalence and predictive factors of sleep apnoea syndrome in type 2 diabetic patients

Sleep apnea is characterized by pauses in breathing during sleep. There are three forms: central, obstructive, and complex, or mixed sleep apnea. Central sleep apnea, a manifestation of respiratory instability in many clinical conditions and with a variety of causes, is the result of a temporary cessation of breathing in which the inhibitory influences favoring the instability predominate over excitatory influences favoring stable breathing. In contrast to central sleep apnea, according to the published data from previous studies, an association exists between obstructive sleep apnea and various comorbidities, especially chronic obstructive pulmonary disease. This article examines retrospectively the possible association of central sleep apnea with special sleep-related symptoms and various co-morbidities. Data of all patients with different types of central sleep apnea were collected from our hospital charts within the Department of Pneumology, HELIOS Clinic, University of Witten/Herdecke, Wuppertal, Germany, within the study period of January 1, 2011 to September 19, 2014. After clinical examination, all patients underwent polysomnography in our sleep laboratory. We identified a total of 60 (3.5 %) patients with central sleep apnea from 1722 patients with assumed sleep disordered breathing of the mean age of 68.2 ± 13.7 years (44 males - 73.3 %, 95 % CI 0.6-0.9 and 16 females - 26.7 %, 95 % CI 0.2-0.4). Typical symptoms of sleep-disordered breathing were not observed. A relation to co-morbidities was not found. Central sleep apnea was often diagnosed in the elderly. A direct association between central sleep apnea and symptoms of sleep-disordered breathing and various co-morbidities was not detected. This is in direct contrast to the obstructive sleep apnea syndrome.

There are no standard therapies for the management of central sleep apnea (CSA). Either positive pressure therapy (PAP) or supplemental oxygen (O(2)) may stabilize respiration in CSA by reducing ventilatory chemoresponsiveness. Additionally, increasing opioid use and the presence of comorbid conditions in US veterans necessitates investigations into alternative titration protocols to treat CSA. The goal was to report on the effectiveness of titration with PAP, used alone or in conjunction with O(2), for the management of CSA associated with varying comorbidities and opioid use. This was a retrospective chart review over 3 years, performed at a VA sleep disorders center. The effects of CPAP, CPAP+O(2), and BPAP+O(2), used in a step-wise titration protocol, on consecutive patients diagnosed with CSA were studied. CSA was diagnosed in 162 patients. The protocol was effective in eliminating CSA (CAI ≤ 5/h) in 84% of patients. CPAP was effective in 48%, while CPAP+O(2) combination was effective in an additional 25%, and BPAP+O(2) in 11%. The remaining 16% were non-responders. Forty-seven patients (29%) were on prescribed opioid therapy for chronic pain, in whom CPAP, CPAP+O(2), or BPAP+O(2) eliminated CSA in 54%, 28%, and 10% cases, respectively. CPAP, CPAP+O(2), and BPAP+O(2) each produced significant declines in the AHI, CAI, and arousal index, and an increase in the SpO(2). The data demonstrate that using a titration protocol with CPAP and then PAP with O(2) effectively eliminates CSA in individuals with underlying comorbid conditions and prescription opioid use. Comparative studies with other therapeutic modalities are required.

Arnold Chiari malformation (ACM) is the most common cause of central sleep apnea (CSA) in otherwise healthy children. Although there are several case reports and series reported on this topic, there are limited descriptions of the long-term course of these children after the surgical interventions. Posterior fossa decompression surgery to relieve pressure of the herniating cerebellum on the brainstem is generally thought to significantly improve CSA in most cases, however, there are very limited data on the natural course of CSA in children following decompression surgery. There may be a subset of children in whom it may take much longer for CSA to resolve, and in some it may not resolve completely. Hence, these children need to be followed closely with sleep studies to document resolution of CSA. In this case report, we describe a 10-year-old male with severe CSA who was subsequently diagnosed with type 1 ACM and underwent posterior fossa decompressive surgery. However after surgery, although there was improvement in his CSA, he still had a significant degree of residual CSA which required bilevel positive pressure therapy and took more than 7.5 years to resolve. This case report illustrates the need for close follow-up in these children and for providers to understand the natural course so they can accurately counsel families about expectations after surgical treatments.

recent enhanced appreciation of sleep-cardiovascular interactions, particularly in patients with congestive heart failure (CHF), has prompted careful consideration of the relevance of sleep-disordered breathing to CHF pathophysiology, progression, and treatment. 1Sleepdisordered breathing may be broadly classified as either obstructive sleep apnea (OSA) or central sleep apnea (CSA). 1 The former is characterized by repetitive collapse of the upper airway, whereas in patients with CHF, the latter is most often due to periodic alternation of diminished ventilatory drive and compensatory hyperventilation typical of Cheyne-Stokes respiration (Figure 1).CSA is likely a consequence rather than a cause of CHF.Although the mechanisms that underlie CSA/Cheyne-Stokes respiration in patients with CHF are not well understood, pulmonary congestion with increased lung J-receptor stimulation and greater chemosensitivity may play a role in the genesis of the periodic breathing that characterizes this disorder. 1,2 Article p 3173Of 5 million North Americans with CHF, an estimated 50% may have coexistent sleep apnea.Although the prevalence of OSA is much higher than CSA in the general population, 3 it appears that this relationship may be reversed among patients with systolic heart failure.Case series have reported frequencies of CSA exceeding 40% for stable, ambulatory patients with CHF in a ratio Ͼ2:1 relative to the frequency of OSA.Indeed, the frequency of OSA in these same series was similar to that observed in the general population, whereas the frequency of CSA was strikingly higher. 4,5Furthermore, in patients with CHF, CSA has been associated with increased morbidity and mortality, [5][6][7] increased neurohormonal activation, 1 increased ventricular arrhythmia, 8 decreased exercise capacity, 5,9 and more advanced New York Heart Association class. 5However, whether these associations merely reflect more advanced CHF or whether repetitive apneas with hypoxia and sympathetic neural activation 10 independently promote disease progression and adverse outcomes remains unknown.

The aim of the study was to investigate the relationship between central sleep apnoea (CSA) at high altitude and arterial blood gas tensions, and by inference, ventilatory responsiveness. Fourteen normal adult volunteers were studied by polysomnography during sleep, and analysis of awake blood gases during ascent over 12 days from sealevel to 5050 m in the Nepal Himalayas. Thirteen subjects developed CSA. Linear regression analysis showed tight negative correlations between mean CSA index and mean values for sleep SaO2, PaCO2 and PaO2 over the six altitudes (r2 > or = 0.74 for all, P < 0.03). Paradoxically there was poor correlation between the individual data for CSA index and those parameters at the highest altitude (5050-m) where CSA was worst (r2 < 0.12 for all, NS), possibly due to variation in degree of acclimatization between subjects. In addition, CSA replaced mild obstructive sleep apnoea during ascent. Obstructive sleep apnoea index fell from 5.5 +/- 6.9/h in rapid eye movement sleep at sealevel to 0.1 +/- 0.3/h at 5050 m (P < 0.001, analysis of variance), while CSA index rose from 0.1 +/- 0.3/h to 55.7 +/- 54.4/h (P < 0.001). There was a general relationship between decreasing PaCO2 and CSA, but there were significant effects from variations in acclimatization that would make hypoxic ventilatory response an unreliable predictor of CSA in individuals.