Central Sleep Apnea
Central sleep apnea (CSA) is characterised by repeated episodes of airflow reduction or interruption due to short decreases or pauses in central ventilatory drive during sleep (Randerath et al., 2017). While it has lower prevalence in the general population than obstructive sleep apnea (OSA), it is overrepresented in specific subpopulations including patients with heart failure, a history of stroke, those receiving opioid medications or continuous positive airway pressure (CPAP) therapy.
Visit different sections of the Sleep Apnea Learning Zone to find out about the incidence of CSA, its pathophysiology, symptoms and diagnosis and current treatment options.
Central sleep apnea epidemiology
In the general population, the prevalence of CSA is less than 1% (Bixler et al., 1998), but it has been reported in 2–37% of patients with heart failure and in 3–72% of patients who have had a stroke (Randerath et al., 2017). Treatment-emergent central sleep apnea (TE-CSA) can also be observed in patients treated with opioids and in patients treated with continuous positive airway pressure (CPAP) (Baillieul et al., 2019).
Who gets central sleep apnea?
As with OSA, CSA is more likely in men than women but there are specific subpopulations in which CSA is over-represented.
Patients with heart failure: CSA is highly prevalent in patients with stable congestive heart failure with reduced ejection fraction (HFrEF) and in those with preserved ejection fraction (HFpEF) (Randerath et al., 2017). Data from a large, long-term, observational study showed increased mortality in hospitalised HFrEF patients with CSA (Cowie et al., 2015; Khayat et al., 2015).
Patients who have suffered a stroke: Evidence shows that CSA is often present in patients following stroke (Randerath et al., 2017). OSA is more prevalent than CSA following stroke and it is likely that CSA is a sequel to extensive cerebrovascular events. Brainstem stroke (comprising at least 10% of all ischaemic strokes) has been shown to predispose CSA (Baillieul et al., 2019).
Patients treated with opioids: While literature in this area is limited, there is solid evidence that CSA and irregular breathing may be induced and maintained by opioids (Randerath et al., 2017). In a study of patients on opioid therapy for chronic pain, CSA was reported in 24% and there was a direct relationship between the central apnea index and the daily dosage of methadone (Webster et al., 2008).
Patients treated with CPAP: CSA may emerge or persist in some patients with OSA treated using CPAP. CSA following CPAP initiation may spontaneously resolve within a few weeks or be persistent (Baillieul et al., 2019).
What are the consequences of central sleep apnea?
Like OSA, CSA is associated with snoring and important complications which include frequent night-time awakenings, excessive daytime fatigue and increased risk of adverse cardiovascular events and mortality (Eckert et al., 2007).
Central sleep apnea pathophysiology
Patients with central sleep apnea (CSA) have a disorder of the mechanisms that control breathing. As opposed to OSA, CSA is characterised by repetitive cessation of ventilation during sleep resulting from lack of ventilatory drive to breathe. Normally, ventilation is tightly regulated to ensure levels of arterial oxygen (PaO2) and carbon dioxide (PaCO2) are maintained within narrow ranges. This is achieved by feedback loops that involve peripheral and central chemoreceptors, intrapulmonary vagal receptors, the respiratory control centres in the brainstem and the respiratory muscles (figure 16).
During wakefulness, behavioural control (signals from cortical areas of the brain influencing respiration like talking or swallowing), involving non-chemical stimuli and awake stimulation to ensure normal arterial blood gases. However, during sleep this is lost and chemical control (particularly PaCO2) becomes the key mechanism in regulating ventilation. CSA is most often seen at the onset of sleep or during non–rapid eye movement (NREM) sleep, when behavioural influence is least (Baillieul et al., 2019).
CSA can be primary (idiopathic CSA) or secondary. Secondary CSA can arise because of Cheyne-Stokes breathing in patients with congestive heart failure, certain medical conditions such as stroke, a drug or substance, or high-altitude periodic breathing (AASM, 2014).
Polysomonographic patterns of central sleep apnea
Analysis of the central breathing pattern can help in identifying the underlying pathophysiology and aetiology (figure 17).
Specific subtypes of CSA can also be distinguished based on waking levels of CO2 (Eckert et al., 2007). In eucapnic/hypocapnic CSA, the underlying mechanism is instability in ventilatory control (Hernandez & Patil, 2016). This manifests typically as low PaCO2 and chronic hyperventilation and high respiratory drive. The breathing cycles show distinct alternation between central apneas or hypopneas (waning) and hyperpneas (waxing) (Baillieul et al., 2019).
Hypercapnic CSA and hypoventilation can arise from:
- functional or anatomical lesions at the level of the respiratory centres reducing ventilatory drive (hypoventilation syndromes and drug-induced hypoventilation)
- an inability to translate the central drive into adequate ventilation (neuromuscular disorders)
In CSA, there are two main determinants of ventilatory control instability, high loop gain and a narrow CO2 reserve (figure 18) (Baillieul et al., 2019).
High loop gain is defined as a disproportional response to a given stimulus which promotes instability. When there is a disturbance, such as hyperventilation, PaCO2 will drop (i) and once the blood gas change is detected, a central apnea event will be initiated to counter the disturbance (ii). This will result in an increase in PaCO2 levels. With high loop gain, each response to a disturbance is greater than the initial disturbance resulting in a corrective hyperpnea (iii) which will send PaCO2 levels towards or below the apnea threshold (Baillieul et al., 2019).
Central sleep apnea symptoms and diagnosis
Central sleep apnea symptoms
The symptoms of CSA are similar to those of OSA (figure 19). While excessive weight and snoring are significant features of OSA, they may not be so prominent in CSA (Naughton & Bradley, 1998).
Central sleep apnea diagnosis
Full polysomnography (PSG) with oesophageal pressure measurement is the gold standard for diagnosing CSA (Randerath et al., 2017). In routine practice, different surrogates of respiration and respiratory effort are used (figure 20).
As we have already discussed, specific PSG patterns can be associated with different clinical entities and they should therefore be described precisely to enable identification of the underlying and often overlapping causes (Baillieul et al., 2019). Separating central from obstructive hypopneas is very challenging when abnormal respiratory events are measured in a sleep study, but this is both crucial and necessary for the diagnosis of CSA.
The International Classification of Sleep Disorders – Third Edition (ICSD-3) specifies that CSA is classified as at least 10 central apneas and hypopneas per hour of sleep together with frequent arousals and fragmented sleep (Sateia et al., 2014).
CSA can be identified by the following criteria during PSG if there is a combination of:
- a drop in the peak signal excursion ≥90% of pre-event baseline measured using a flow sensor
- the duration of the ≥90% drop is ≥10 seconds.
In contrast to an obstructive event, the classification of an apnea as central is based on there being no ventilatory effort during the event (Berry et al., 2012).
Hypopneas are identified by a combination of:
- a drop in the peak signal excursion ≥30% of pre-event baseline
- the duration of the ≥30% drop is ≥10 seconds
- a ≥3% oxygen desaturation from pre-event baseline or arousal.
Central hypopneas are characterised by a temporary reduction in ventilatory effort during sleep (Berry et al., 2012).
Current central sleep apnea treatment options
There are treatment options for CSA, but as CSA has a number of causes it is important to identify the underlying cause to guide treatment.
Given that oxygen saturation levels fall during night-time apneic events, it is reasonable to assume that giving supplemental oxygen would maintain oxygen levels in the normal range. Certainly, supplemental oxygen has been shown to reduce the AHI by 37–85% in stable HFrEF with CSA (Randerath et al., 2017). However, while oxygen therapy may reduce CSA, hypoxia and left ventricular ejection fraction, in heart failure, the currently available evidence does not support its use long-term (Randerath et al., 2017).
Acetazolamide is a mild diuretic agent that causes metabolic acidosis. It was hypothesised to reduce the likelihood of developing CSA by shifting the apneic threshold of PaCO2 to a lower level. In a single, double-blind study, acetazolamide showed improvement in subjective sleep quality and decreased both the respiratory events and nocturnal oxygen desaturation. However, it did not show any improvement in left ventricular ejection fraction or in the objective measurement of sleep quality (Javaheri et al., 2016). Acetazolamide has been shown to be effective therapy in primary central sleep apnea and Cheyne-Stokes breathing in patients with heart failure and in the treatment of high-altitude periodic breathing, but it is not recommended currently (Bekfani & Abraham, 2016).
Continuous positive airway pressure
Findings from short-term clinical trials have shown that CPAP can alleviate CSA, improve LVEF and quality of life (Randerath et al., 2017). However, there has only been one long-term, multi-centre clinical trial of CPAP in HRrEF and CSA. This Canadian trial reduced the AHI by 53% but with residual CSA persisting in 43% of the patients (Bradley et al., 2005). CPAP is minimally effective in CSA and is a more suitable treatment for obstructive sleep apnea.
Adaptive servo-ventilation (ASV) devices have been specifically designed to treat CSA (Baillieul et al., 2019). ASV therapy differs from CPAP or BPAP by providing dynamic (i.e. breath-by-breath) adjustment of inspiratory pressure support (IPS) and utilising an auto-backup rate to normalise breathing rate relative to a predetermined target (Aurora et al., 2016). These devices (figure 21) continually measure either minute ventilation or peak airflow amplitude and they use algorithms to target a specific level of ventilation which is achieved using just enough positive airway pressure (Javaheri et al., 2014). Res Med ASV devices use a three-minute moving average to monitor and determine an appropriate target minute ventilation, set to 90% of their most recent minute ventilation (Aurora et al., 2016). Philips Respironics ASV device utilises inspiratory flow as the primary variable to identify and respond to sleep-related breathing disorders (SRBD). In the absence of SRBD, the algorithm identifies and responds to obstructive sleep disordered breathing events as they occur by increasing the expiratory positive airway pressure (EPAP). During periods of airway stability, the algorithm will proactively assess the airway to minimise pressure while maintaining upper airway patency (Aurora et al., 2016).
Studies have demonstrated that ASV is superior to CPAP therapy for controlling the number of CSA events, improving sleep architecture and daytime hypersomnolence, particularly for Cheyne-Stokes breathing (Philippe et al., 2006; Allam et al., 2007). Indeed, in one study, both ASV and CPAP decreased the apnea-hypopnea index (AHI), but only ASV completely corrected Cheyne-Stokes breathing by attaining an AHI below 10/h (Philippe et al., 2006). ASV treatment guidelines do not recommend ASV in patients with CSA related to heart failure with reduced ejection fraction (HFrEF) (Aurora et al., 2016). This is because the SERVE-HF clinical trial showed that ASV was associated with increased all-cause and cardiovascular mortality (Cowie et al., 2015). However, some aspects of the SERVE-HF trial were controversial and there was low compliance with the ASV treatment (Baillieul et al., 2019).
While the Philips ASV device is not specifically indicated for the treatment of patients with heart failure, recent publications have demonstrated that, during PSG (acutely) as well as over the longer term (up to 12 months), ASV reduces the total apnea hypopnea index, and central apnea index to clinically acceptable levels in patients with heart failure (Lee-Chiong et al., 2015). Indeed, The European Task Force on Central Sleep Apnoea recommends that ASV can be used in CPAP non-responders with symptomatic central sleep apnoea and left ventricular ejection fraction (LVEF) > 45% but not in predominant CSA and LVEF ≤45% (Randerath et al., 2017). That being said, there may be some patients with HFrEF that will respond well to ASV.
Visit the Sleep and Breathing conference 2019 section to learn more about the encouraging compliance data in the ADVENT-HF trial. Dr Elisa Perger describes the effects of ASV on mortality and morbidity in patients with CSA, OSA and heart failure.
A treatment algorithm for the different types of CSA has been suggested (figure 22).
Central sleep apnea disease awareness references
Allam JS, Olson EJ, Gay PC, Morgenthaler TI. Efficacy of adaptive servoventilation in treatment of complex and central sleep apnea syndromes. Chest. 2007;132(6):1839–46.
American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed, American Academy of Sleep Medicine, Darien, IL 2014.
Aurora RN, Bista SR, Casey KR, Chowdhuri S, Kristo D et al. Updated adaptive servo-ventilation recommendations for the 2012 AASM guideline: “The treatment of central sleep apnea syndromes in adults: Practice parameters with an evidence-based literature review and meta-analyses”. J Clinical Sleep Med. 2016;12(5):757–61.
Baillieul S, Revol B, Jullian-Desayes I, Joyeux-Faure M, Tamisier R, Pépin JL. Diagnosis and management of central sleep apnea syndrome. Expert Rev Respir Med. 2019;24:1–13.
Bekfani T, Abraham WT. Current and future developments in the field of central sleep apnoea. Europace. 2016;18(8):1123–34.
Berry RB, Budhiraja R, Gottlieb DJ, Gozal D, Iber C, Kapur VK et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med. 2012;8(5):597–619.
Bixler EO, Vgontzas AN, Ten Have T, Tyson K, Kales A. Effects of age on sleep apnea in men: I. Prevalence and severity. Am J Respir Crit Care Med. 1998;157(1):144–8.
Bradley TD, Logan AG, Kimoff RJ, Sériès F, Morrison D, Ferguson K et al. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med. 2005;353(19):2025–33.
Cherniack NS, Longobardo G, Evangelista CJ, (2005). Causes of Cheyne - Stokes respiration. Neurocritical Care. 2005;3(3) :271–279.
Cowie MR, Woehrle H, Wegscheider K, Angermann C, d'Ortho MP, Erdmann E, Levy Pet al. Adaptive servo-ventilation for central sleep apnea in systolic heart failure. N Engl J Med. 2015;373(12):1095–1105.
Eckert DJ, Jordan AS, Merchia P, Malhotra A. Central sleep apnea: Pathophysiology and treatment. Chest. 2007;131(2):595–607.
Hernandez AB, Patil SP. Pathophysiology of central sleep apneas. Sleep Breath. 2016;20(2):467–82.
Javaheri S. Acetazolamide improves central sleep apnea in heart failure: a double-blind, prospective study. Am J Respir Crit Care Med. 2006;173(2):234–7.
Javaheri S, Brown LK, Randerath WJ. Positive airway pressure therapy with adaptive servoventilation: part 1: operational algorithms. Chest. 2014;146(2):514–523.
Khayat R, Jarjoura D, Porter K, Sow A, Wannemacher J, Dohar R et al. Sleep disordered breathing and post-discharge mortality in patients with acute heart failure. Eur Heart J. 2015;36(23):1463–9.
Lee-Chiong T, Needham C, Hardy W. Clinical update of BiPAP autoSV for treatment of sleep disordered breathing. Philips white paper, September 2015. Available at: http://a360-wp-uploads.s3.amazonaws.com/wp-content/uploads/sleeprev/2016/02/BiPAPAutoSVforSDB.pdf (accessed May 2019).
Mayo Clinic. Central sleep apnea. 2019. Available at: https://www.mayoclinic.org/diseases-conditions/central-sleep-apnea/symptoms-causes/syc-20352109 (accessed May 2019).
Naughton MT, Bradley TD. Sleep apnea in congestive heart failure. Clin Chest Med. 1998;19(1):99–113.
Philippe C, Stoïca-Herman M, Drouot X, Raffestin B, Escourrou P, Hittinger L et al. Compliance with and effectiveness of adaptive servoventilation versus continuous positive airway pressure in the treatment of Cheyne-Stokes respiration in heart failure over a six-month period. Heart. 2006;92(3):337–42.
Randerath W, Verbraecken J, Andreas S, Arzt M, Bloch KE, Brack T, Buyse B et al. Definition, discrimination, diagnosis and treatment of central breathing disturbances during sleep. Eur Respir J. 2017;49: 1600959.
Sateia MJ. International Classification of Sleep Disorders-Third Edition. Chest. 2014;146(5):1387–1394.
Webster LR, Choi Y, Desai H, Webster L, Grant BJ. Sleep-disordered breathing and chronic opioid therapy. Pain Med. 2008;9(4):425–32.