Cheyne–Stokes Respiration During Sleep: Mechanisms and Potential Interventions

Symposium on Respiratory Medicine

Cheyne–Stokes respiration during sleep: mechanisms and potential interventions

Cheyne–Stokes respiration is characterized by a typical waxing and waning pattern in breathing amplitude, interspersed with central apnoeas or hypopnoeas. This article reviews current knowledge regarding Cheyne–Stokes respiration with a particular emphasis on the mechanisms and latest methods of intervention.

heyne–Stokes respiration is a form of central Mechanisms sleep-disordered breathing in which there are Normal function Ccyclical fluctuations in breathing. These lead to The pathophysiological mechanism leading to Cheyne– periods of central apnoeas and hypopnoeas, which alter- Stokes respiration is very complex, but the instability in nate with periods of hyperpnoea in a gradual waxing respiratory drive results in fluctuation of PaCO2 around and waning fashion. Cheyne–Stokes respiration is asso- the apnoeic threshold. Hyperventilation and PaCO2 below ciated with changing arterial partial pressures of oxygen the apnoeic threshold trigger a central apnoea. The cre- (PaO2) and carbon dioxide (PaCO2) (AlDabal and scendo–decrescendo pattern of respiration in Cheyne– BaHammam, 2010). Cheyne–Stokes respiration is Stokes respiration is a compensation for the changing levels believed to mirror an underlying cardiac disease with of blood O2 and CO2 (AlDabal and BaHammam, 2010). subsequent negative consequences for the cardiac dis- ease (Oldenburg et al, 2014a). Central sleep apnoea and Pathological changes Cheyne–Stokes respiration occur in 30–50% of patients When respiratory disorders develop, resulting in changes with congestive heart failure (Noda et al, 2013). There to levels of PaCO2 and PaO2, this is detected and stimu- is an increase in the prevalence of Cheyne–Stokes respi- lates feedback regulation, which increases or decreases ration when the severity of heart failure increases and ventilation accordingly. The PaCO2 can be corrected cardiac function decreases (Bitter et al, 2009). At the gradually and active adjustment stops after this returns to same time, the presence of Cheyne–Stokes respiration the normal range, keeping ventilation at a stable level. accelerates the progression of congestive heart failure, However, changes in PaCO2 may not feed back to the which is associated with increased mortality and mor- CNS in a timely manner, and active ventilation regula- bidity and has a significant impact on quality of life tion persists which may lead to overcorrection of PaCO2. (Duning et al, 2013). At this time, if PaCO2 falls below the apnoeic threshold, Several physiological or pathological factors influence apnoea appears (Badr, 2009). the susceptibility to Cheyne–Stokes respiration including The normal PaCO2 level during sleep is about 6.0 kPa sex (male), age (>60 years old), PaCO2 (5.0 kPa) and a (the eucapnic sleep PaCO2 level) and the apnoeic thresh- history of atrial fibrillation (Noda et al, 2013). Some old is usually 0.27–0.80 kPa lower. The sleep apnoeic diseases increase susceptibility to Cheyne–Stokes respira- threshold is equal to or marginally lower than the wake- tion, including those causing a dysfunction of central fulness eucapnic PaCO2 level (Eckert et al, 2007). The respiratory control centres in the brainstem (strokes, difference between the eucapnic sleep PaCO2 level and traumatic brain injuries and brain tumours) (Duning et the apnoeic threshold is critical in the development of al, 2013; Noda et al, 2013), pulmonary hypertension Cheyne–Stokes respiration: the smaller the difference, (Ulrich et al, 2008) or end-stage renal failure (Perl et al, the more likely the occurrence of Cheyne–Stokes respira- 2006). tion (Randerath, 2009). Factors including hypocapnia, arousal, chemoreceptor Dr Yan Wang* is Consultant, Dr Jie Cao* is Consultant, Professor Jing Feng sensitivity enhancement and the prolonging of circulat- is Chief Physician and Professor Bao-Yuan Chen is Chief Physician in the ing time may lead to instability of the respiratory control Department of Respiratory Diseases, Tianjin Medical University General Hospital,

system (Figure 1). Ltd Tianjin, 300052, China Hypocapnia Correspondence to: Professor J Feng ([email protected]) Healthcare In normal conditions, a certain concentration of CO *Dr Y Wang and Dr J Cao are joint first authors, 2 MA can stimulate chemoreceptors and is necessary for main- and contributed equally to this work 2015 tenance of normal breathing. When PaCO2 decreases ©

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excessively, the CO2-dependent stimulation of respirato- patients with heart failure. In the early stages of conges- ry drive will be reduced or even eliminated, leading to tive heart failure, the chemoreflex acts as a compensatory Cheyne–Stokes respiration. In patients with Cheyne– mechanism. Later, however, it helps to sustain the sympa- Stokes respiration, the PaCO2 level is close to the eucap- thetic activation, with detrimental effects on cardiovascu- nic sleep PaCO2 level. Therefore, the respiratory control lar function and prognosis (Passino et al, 2010). system in these patients is not stable and a slightly Peripheral chemoreceptors include the carotid body increase in ventilation may cause PaCO2 to be less than and the aortic body. Central chemoreceptors are located the threshold. In patients with chronic heart failure, left on the surface of the medulla oblongata. They regulate ventricular volume and perfusion pressure increases, respiration through changes in PaO2 and hydrogen ion which worsens pulmonary congestion and pulmonary (H+) concentration. In patients with congestive heart oedema, elevates pulmonary capillary wedge pressure, failure, carotid body chemoreceptor activity is enhanced enhances J-receptor and C fibre sensor stimulation and and is associated with oscillatory breathing (Cheyne– ultimately leads to excitation of respiratory drive (AlDabal Stokes respiration) patterns, increased sympathetic and BaHammam, 2010). The increased sympathetic nerve activity and increased arrhythmia incidence. activity in patients with chronic heart failure as a com- Yumino and Bradley (2008) showed that the central and pensation for cardiac pump failure, together with hypox- peripheral chemoreceptor excitability in patients who aemia resulting from obstructive apnoea often as a have heart failure and Cheyne–Stokes respiration, comorbidity of heart failure, can also lead to hyperventi- whether during waking or sleeping, is higher than those lation and hypocapnia. without any sleep-disordered breathing or only with obstructive sleep apnoea. Chemoreceptor sensitivity Arousal enhancement means that these patients may suffer dras- Arousal from sleep is an important protective response in tic reactions to tiny blood PaCO2 changes, leading to order to restore gas exchange, but it can lead to respiratory apnoea or hypoventilation. control instability. A low arousal threshold may be more Some hormones and drugs affect chemoreceptor sensi- likely to lead to a repetitive Cheyne–Stokes respiration tivity. Adrenaline or noradrenaline can excite carotid cycle as the individual oscillates between wakefulness and body chemoreceptors because they cause local vasocon- sleep. Some respiratory events, hypoxaemia, periodic leg striction and reduce the blood flow to the carotid body, movements in sleep, spontaneous awakening, pain, gastro- leading to hypoxia and then ischaemia. Circulating con- oesophageal reflux disease and insomnia can all lead to centrations of catecholamine increase in patients with arousals. Sleep state conversion and lower arousal threshold congestive heart failure and the peripheral chemoreceptor may be sufficient to promote Cheyne–Stokes respiration. sensitivity will increase as well (Brack et al, 2012). In a A CO2 level which has reached the threshold during sleep can lead to hypercapnia compared to a relatively Figure 1. The main mechanisms and interrelation of Cheyne–Stokes respiration. lower CO2 level which would trigger this during arousal, thus triggering hyperventilation, and ultimately leading to Chronic congestive heart failure Cheyne–Stokes respiration. If patients immediately go into the sleep stage after arousals, and this is followed by hyper- ventilation which may persist for a while, the PaCO2 will Some respiratory Left ventricular Sympathetic Left rapidly fall below the sleep apnoeic threshold, causing events, volume and activity ↑ ventricular Cheyne–Stokes respiration again and leading to a series of hypoxaemia, perfusion pressure ejection Cheyne–Stokes respiration cycles (Malhotra and Owens, periodic leg ↑, pulmonary fraction 2010). So arousals may play a key role in maintenance of movements in congestion, and stroke Functional sleep, spontaneous pulmonary capillary volume ↓ residual hyperventilation in Cheyne–Stokes respiration. Pinna et al Catecholamine (2012) showed that fluctuations in sleep/wake state are an awakening, pain, wedge pressure ↑ capacity ↓, gastro-oesophageal release ↑ upper airway important mechanism contributing to the development of reflux disease and instability ↑ oscillatory breathing patterns in patients with congestive insomnia Activate J receptors heart failure. Domenico Pinna et al (2014) also found that and C fibre sensors Circulating transitions between wakefulness and non-rapid eye move- Chemoreceptor time ↑ ment sleep paralleled apnoeic events during Cheyne– sensitivity ↑ Stokes respiration in patients with heart failure. They Hyperventilation concluded that the relationships between state changes and Arousal

Ltd respiratory events are consistent with the notion that state Hypocapnia fluctuations promote ventilatory instability.

Healthcare Chemoreceptor sensitivity enhancement MA The pathophysiological role of enhanced chemosensitiv- Respiratory control system instability 2015

© ity to CO2 and/or hypoxia has been emphasized in

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study on rabbits with pacing-induced congestive heart (Farré et al, 2004), which is regarded as a ‘gold’ standard. failure Marcus et al (2014) demonstrated that denerva- Features of Cheyne–Stokes respiration seen on polysom- tion of the carotid body reduces renal sympathetic nerve nography include: activity, sympatho-respiratory coupling and arrhythmia n The typical crescendo–decrescendo model of central incidence, while improving breathing stability and car- apnoea or hypopnoea, which predominantly occurs in diac function. stage 1 and 2 of non-rapid eye movement sleep n O2 desaturation is usually mild (<80–85%) Prolonged circulation time n Arousal usually appears at the strong peak of breathing The circulation time is inversely proportional to stroke n The respiratory cycle is generally >45 s (proportional volume and cardiac output. Patients with chronic conges- to lung–chemoreceptor cycle time, but inversely pro- tive heart failure have decreased left ventricular ejection portional to cardiac output) fraction (McGee, 2013) and stroke volume, so their circu- n Apnoeas are worse in the supine position during sleep. lation time increases. This delays delivery of information In the ‘Update of the 2007 AASM Manual for the on blood gases to the chemoreceptors which thus delays Scoring of Sleep and Associated Events’ (Berry et al, feedback input to the respiratory centre (Momomura, 2012), Cheyne–Stokes respiration in adults is scored 2012). The respiratory control system will be instable, when both of the following are met: which may change negative feedback to positive feedback 1. There are episodes of three or more consecutive cen- and cause hyperventilation, thus causing the crescendo– tral apnoeas and/or central hypopnoeas separated by a decrescendo respiratory pattern (Lorenzi et al, 2005). crescendo and decrescendo change in breathing ampli- tude with a cycle length of at least 40 s (typically Others 45–90 s) Patients with congestive heart failure have a low func- 2. There are five or more central apnoeas and/or central tional residual capacity as a result of pulmonary conges- hypopnoeas per hour associated with the crescendo– tion, cardiomegaly, pleural effusion or the fluid shift from decrescendo breathing pattern recorded over a mini- a standing to supine position (Wilcox et al, 2015). Thus mum of 2 hours’ monitoring. the lung O2 and CO2 reservoir is decreased, which may contribute to instability of the respiratory control system Potential interventions (Lorenzi et al, 2005). In addition, muscle tone decreases Since Cheyne–Stokes respiration occurs as a consequence when sleeping, rendering the upper airway prone to col- of heart failure, optimization of heart failure is essential to lapse and thus causing hypoventilation. During arousals, treat this – improving cardiac function may ameliorate the upper airway patency is reestablished, resistance is Cheyne–Stokes respiration. Diuretics and angiotensin- reduced and hyperventilation occurs (Lorenzi et al, 2005; converting enzyme inhibitors can ease pulmonary vascular Badr, 2009). This results from sleep-awake transitions and congestion, decrease preload and afterload, improve oxy- may also lead to respiratory control instability and fluc- genation and minimize overshoot. Beta blockers can less- tuations of PaCO2 above or below the apnoeic threshold. en sympathetic overstimulation and decrease afterload. Besides drugs, methods such as electrical stimulation, Clinical manifestation and diagnosis atrial overdrive pacing and cardiac resynchronization with The signs of Cheyne–Stokes respiration are similar to those biventricular pacemakers have all been reported to reduce of obstructive sleep apnoea such as excessive daytime Cheyne–Stokes respiration in patients with heart failure, sleepiness, frequent arousals during sleep with choking, and improve their sleep quality, life quality and cardiac morning fatigue and headaches, and complaints of sleep- pump function as well as prognosis (Brack et al, 2012). lessness. These may be partially masked by the manifesta- In addition, many other methods including oxygen tions of congestive heart failure (Kazimierczak et al, 2013). therapy, positive airway pressure, sedative-hypnotic medi- Patients with severe Cheyne–Stokes respiration have a sig- cations, theophylline and exogenous CO2 can smooth nificantly increased prevalence of non-sustained ventricu- Cheyne–Stokes respiration (Table 1). However, the thera- lar tachycardia and other arrhythmias compared to patients peutic effect on Cheyne–Stokes respiration is not gener- with mild or no Cheyne–Stokes respiration (Lanfranchi et ally hopeful. A meta-analysis by Aurora et al (2012) al, 2003) as a result of increased sympathetic activity dur- showed that the main treatments for Cheyne–Stokes res- ing the hyperpnoeic phase of Cheyne–Stokes respiration. piration caused by congestive heart failure are continuous In addition, patients with severe Cheyne–Stokes respira- positive airway pressure, adaptive servo ventilation and tion have reduced heart rate variability, which suggests nocturnal oxygen therapy, while bi-level positive airway

autonomic dysfunction (Leung et al, 2003). pressure, acetazolamide and theophylline are options. Ltd As many symptoms are also common in patients with obstructive sleep apnoea, diagnosis of Cheyne–Stokes Continuous positive airway pressure Healthcare respiration requires nocturnal polysomnography and Mechanisms by which continuous positive airway pres- MA accurate detection of flow, measurement of oxyhaemo- sure reduces Cheyne–Stokes respiration may include 2015

globin saturation and detection of respiratory effort preventing pharyngeal narrowing during central apnoea, ©

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stabilizing respiratory drive, reducing respiratory events, apnoea–hypopnoea index. Repeated titration of contin- improving oxygenation by increasing lung volume, uous positive airway pressure is also important, which improving cardiac function, decreasing preload by reduc- may determine any benefits of long-term treatment ing venous blood backflow to the right atrium and after- (Arzt et al, 2007). load by increasing intrathoracic pressure, improving left ventricular ejection fraction and mitral regurgitation. Adaptive servo ventilation The Canadian Continuous Positive Airway Pressure for Adaptive servo ventilation is the most effective treatment patients with Central Sleep Apnea and Heart Failure Trial for Cheyne–Stokes respiration and is well tolerated. (CANPAP) was a multicentre randomized controlled While continuous positive airway pressure reduces clinical trial in 258 patients who had heart failure and Cheyne–Stokes respiration by 50% on average, adaptive central sleep apnoea and were receiving optimal medical servo ventilation normalizes it in most patients. In a mul- therapy. The trial showed that continuous positive airway tinational, multicentre, randomized, parallel group study, pressure could improve nocturnal oxygenation, left ven- use of adaptive servo ventilation improved multiple inter- tricular ejection fraction and 6-minute walking distance, mediate cardiorespiratory end points, including the time and lower plasma noradrenaline concentrations, but it to first event of all-cause death, unplanned hospitaliza- had no effect on survival without a heart transplant (Arzt tion (or unplanned prolongation of a planned hospitali- et al, 2007). zation) for worsening congestive heart failure, cardiac In a post-hoc stratified analysis, transplant-free sur- transplantation, resuscitation of sudden cardiac arrest, or vival and left ventricular ejection fraction were improved appropriate life-saving shock for ventricular fibrillation in patients in whom continuous positive airway pressure or fast ventricular tachycardia in patients who have an suppressed the apnoea–hypopnoea index to less than implantable cardioverter defibrillator (Cowie et al, 2013). 15/h, but were not improved in patients without this Adaptive servo ventilation devices apply different lev- level of suppression. Therefore polysomnography should els of pressure support: during periods of hypoventila- be repeated within 1–3 months of beginning continuous tion the inspiratory pressure is increased and during positive airway pressure to assess its effect on the hyperventilation it is reduced to the lowest possible level.

Table 1. Treatment suggestions for Cheyne–Stokes respiration

Study Recommended Alternative Not recommended

Eckert et al (2007) CPAP Larger trials are required to determine its long-term efficacy and safety of O2 therapy Acetazolamide, theophylline and inhalation of CO2

Badr (2009) CPAP, ASV, O2 BiPAP may aggravate the severity of central apnoea, acetazolamide and theophylline Inhalation of CO2 remain uncommon, additional studies are needed

AlDabal and ASV BiPAP is a good alternative treatment in patients who are unresponsive or cannot tolerate CPAP. O2, acetazolamide, temazepam, BaHamman Large, multicentre controlled studies are needed to further investigate inhalation of CO2 (2010) potential benefits of CPAP and theophylline

Brack et al (2012) CPAP, ASV O2 may be reserved for patients who can not tolerate non-invasive ventilation, BiPAP, theophylline, acetazolamide only be tried in selected patients under careful supervision pentobarbital, inhalation of CO2

Momomura (2012) CPAP, ASV, O2 BiPAP is more effective than CPAP in treating Cheyne–Stokes respiration, but has low compliance, Acetazolamide, furosemide, and cannot replace CPAP. The effect of chronic phrenic nerve stimulation (which requires surgery) theophylline, atrial overdrive is not known. Dynamic CO2 administration might be developed to treat central sleep apnoea pacing

Aurora et al (2012) CPAP, ASV, O2 To be considered for BiPAP only if there is no response to adequate trials of CPAP, ASV and O2. Acetazolamide and theophylline are considered if positive airway pressure therapy is not tolerated, or accompanied by close clinical follow-up

Oldenburg (2012) ASV, O2 Unilateral phrenic nerve stimulation is a relatively new treatment method, Acetazolamide, theophylline, but further studies are needed to confirm its long-term efficacy inhalation of CO2

Selim et al (2012) CPAP, ASV O2 may be an effective therapy, but less reliably effective than positive airway pressure. Acetazolamide and theophylline are considered if positive airway pressure or O2 is not effective

Noda et al (2013) CPAP, O2, ASV BiPAP could be effective in patients with cardiac dysfunction or heart failure complicated with sleep-disordered breathing and should be considered as a non-pharmacological adjunct

Ltd to conventional drug therapy

Kazimierczak et al CPAP, ASV BiPAP is intended for patients who do not tolerate CPAP well. Phrenic nerve stimulation O2, acetazolamide, theophylline

Healthcare (2013) is the most recently developed method, but further studies are ongoing to assess the

MA outcomes and safety of long-term treatment

2015 ASV = adaptive servo ventilation; BiPAP = bi-level positive airway pressure; CO2 = carbon dioxide; CPAP = continuous positive airway pressure; O2 = oxygen ©

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The devices deliver an expiratory pressure to overcome Bi-level positive airway pressure upper airways obstruction. Pressure support is defined Bi-level positive airway pressure can provide appropriate by the difference between expiratory and inspiratory alveolar ventilation when apnoea occurs, thus reducing pressure (Randerath, 2009). Spontaneous inspiration is hyperventilation and secondary apnoea, but may lower supported with varying amounts of inspiratory positive blood PaCO2, which can increase the risk of Cheyne– airway pressure (a relatively higher level). If spontaneous Stokes respiration (Badr, 2009). The S/T mode is used inspiration ceases, adaptive servo ventilation will increase more frequently but the evidence is limited and results inspiratory support (pressure) or provide back-up venti- are conflicting. S/T mode bi-level positive airway pres- lation using an adjusted back-up respiration rate. If sure should only be considered to treat Cheyne–Stokes spontaneous inspiration then increases, support will respiration in those who fail continuous positive airway gradually reduce, to an expiratory positive airway pres- pressure, adaptive servo ventilation and oxygen therapy, sure level if necessary. This reduces nocturnal hyperven- as there is more evidence supporting the use of these tilation as shown by normalization of PaCO2 (Carnevale options. et al, 2011). Effects of adaptive servo ventilation in patients with Nocturnal oxygen therapy congestive heart failure include reducing heart rate and Oxygen therapy may increase the O2 supply to the left blood pressure during the initial 30 minutes of treatment, ventricle, reduce reflex activation of the peripheral chem- and increasing cardiac output in patients with elevated oreceptors (Yumino et al, 2009), ameliorate hypoxaemia, filling pressures as a long-term effect (Haruki et al, 2011). minimize the subsequent ventilation overshoot and alle- Adaptive servo ventilation can also suppress respiratory viate central apnoea by increasing cerebral partial pressure events more effectively than oxygen therapy, continuous of CO2 through the Haldane effect (Solin et al, 1999). positive airway pressure or bi-level positive airway pres- However, oxygen therapy may cause hyperoxia and sure. It can also improve respiratory control, New York increase the generation of oxygen free radicals and, hence, Heart Association functional class (Hetland et al, 2013), induce oxidative stress. This can exert adverse haemody- quality of life, cardiac function, symptoms, exercise namic effects such as raising vascular resistance, blood capacity and N-terminal pro-brain natriuretic peptide pressure and left ventricular filling pressure and lowering concentrations (Bitter et al, 2010), and reduce the risk of cardiac output (Haruki et al, 2011). In general, the life-threatening arrhythmias. advantages of O2 supplementation in treating Cheyne– Some patients suffer co-existing obstructive sleep Stokes respiration may outweigh these potential disad- apnoea and Cheyne–Stokes respiration rather than pure vantages (Aurora et al, 2012). While oxygen therapy does Cheyne–Stokes respiration, and adaptive servo ventila- not confer outcome advantages over continuous positive tion effectively suppresses most types of respiratory airway pressure according to available evidence, supple- disturbances and improves sleep and life quality. mental O2 can be easily given to individuals with Adaptive servo ventilation also improves prognosis in Cheyne–Stokes respiration who are unable to comply patients with congestive heart failure who have a cardiac with continuous positive airway pressure. resynchronization therapy defibrillator. Patients with Cheyne–Stokes respiration who have had a cardiac Carbon dioxide inhalation resynchronization therapy defibrillator implanted will Delivery of constant CO2 is effective in eliminating benefit from adaptive servo ventilation (Miyata et al, Cheyne–Stokes respiration by raising PaCO2, but there 2012). are serious concerns about the potential side effects, such The latest generation enhanced adaptive servo ventila- as unwanted elevations in ventilation, work of breathing, tion device (AirCurve 10 CS PaceWave, ResMed and sympathetic nerve activity, and thus CO2 inhalation Company, Australia) has a new feature – auto-adjustment therapy has not been recommended as a routine option of expiratory positive airway pressure. Oldenburg et al for therapy. However, studies into CO2 inhalation thera- (2014b) showed that enhanced adaptive servo ventilation py may reshape its role (Wan et al, 2013). Approaches is non-inferior to adaptive servo ventilation with fixed like inhalation of supplemental CO2 to elevate PaCO2 expiratory positive airway pressure in patients with con- above the apnoeic threshold remain experimental because gestive heart failure and Cheyne–Stokes respiration, with it may cause sympathetic stimulation and long-term a trend towards better control of respiratory events. But clinical trials are lacking (Brack et al, 2012). adaptive servo ventilation is relatively expensive, which restricts its wide application. Moreover, the variability in Phrenic nerve stimulation

response to adaptive servo ventilation in a given patient To date, treatment of Cheyne–Stokes respiration with Ltd along with the myriad choices of specific models and set- adaptive servo ventilation is recommended as the gold tings requires a high degree of expertise from the clini- standard. However, 15–20% of patients with congestive Healthcare cian. Randomized controlled studies are needed to deter- heart failure do not tolerate or do not want any positive MA mine the long-term clinical efficacy of these devices airway pressure therapy. In these patients, phrenic nerve 2015

(Javaheri et al, 2014). stimulation might be an alternative (Oldenburg et al, ©

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2014c). The initial study suggested that after transcuta- nia/hypocapnia, and changes in intrathoracic pressure, neous phrenic nerve stimulation, the apnoea–hypopnoea have harmful effects on the cardiovascular system, and index decreased in patients with heart failure who have the presence of Cheyne–Stokes respiration is associated Cheyne–Stokes respiration and oxygenation was also with increased mortality and morbidity in subjects with improved (Zhang et al, 2012). Zhang et al (2012) variable degrees of heart failure (AlDabal and BaHammam, showed that in a small group of patients with congestive 2010). Severe central sleep apnoea in patients with con- heart failure and Cheyne–Stokes respiration, one night of gestive heart failure is associated with elevated levels of unilateral transvenous phrenic nerve stimulation C-reactive protein, a systemic marker of inflammation improved indices of Cheyne–Stokes respiration and was and cardiovascular risk. This might partly explain the not associated with adverse events. Its short-term applica- negative prognostic impact of Cheyne–Stokes respiration tion is obvious but further studies are needed to confirm in these patients (Schmalgemeier et al, 2014). In short, its long-term safety and efficacy. Cheyne–Stokes respiration is an independent marker of poor prognosis and may ultimately increase the mortality Pharmacological treatment in patients with heart failure. Correct pharmacological treatment of congestive heart failure decreases the severity of Cheyne–Stokes respira- Conclusions tion. Acetazolamide is a mild diuretic and respiratory Cheyne–Stokes respiration has a high prevalence in stimulant. It can inhibit carbonic anhydrase activity, patients with chronic congestive heart failure. The pres- increase urinary excretion of HCO3-, increase the blood ence and severity of Cheyne–Stokes respiration is a mir- concentration of H+, stimulate the respiratory centre and ror for heart function and affects the overall prognosis of reduce the peripheral and central chemoreceptor sensitiv- patients with chronic congestive heart failure. Although ity, to treat Cheyne–Stokes respiration. However, it can- the potential mechanisms of Cheyne–Stokes respiration not improve haemodynamic parameters or the quality of are still under debate, it is important to understand these sleep. In addition, it may also cause hypokalaemia, which mechanisms and provide effective clinical interventions has a proarrhythmic effect (Kazimierczak et al, 2013). where possible. More research is necessary to further Theophylline, a stimulant of the respiratory centre that evaluate the effectiveness of all interventions. BJHM increases its sensitivity to hypercapnia, has been consid- ered a potentially beneficial agent because it can increase This article was supported by grants from the National Natural Science cardiac contractility, dilate coronary arteries, loosen bron- Foundation of China (No. 81270144, 30800507, 81170071). chial smooth muscle and increase respiratory drive in Conflict of interest: none. patients with heart failure (AlDabal and BaHammam, 2010). However, the use of theophylline is limited by its AlDabal L, BaHammam AS (2010) Cheyne-Stokes respiration in patients with heart failure. Lung 188: 5–14 (doi: 10.1007/s00408- adverse effects, mainly cardiac arrhythmias that may 009-9200-4) increase the risk of sudden death, making the long-term Arzt M, Floras JS, Logan AG et al (2007) Suppression of central sleep effect not clear (Kazimierczak et al, 2013). apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Sedative-hypnotic medications such as zolpidem and Continuous Positive Airway Pressure for Patients with Central triazolam may stabilize ventilation through suppressing Sleep Apnea and Heart Failure Trial (CANPAP). Circulation 115: arousals, but they cannot reduce the frequency of 3173–80 Aurora RN, Chowdhuri S, Ramar K et al (2012) The treatment of Cheyne–Stokes respiration. They should only be consid- central sleep apnea syndromes in adults: practice parameters with ered for the treatment of primary central sleep apnoea if an evidence-based literature review and meta-analyses. Sleep 35: the patient does not have underlying risk factors for res- 17–40 (doi: 10.5665/sleep.1580) piratory depression (Aurora et al, 2012). Haack et al (2014) found that simvastatin treatment KEY POINTS ameliorated carotid body chemoreflex sensitivity as well n Cheyne–Stokes respiration is characterized by a typical waxing and waning pattern as increased respiratory variability, apnoea–hypopnoea in breathing amplitude, interspersed with central apnoeas or hypopnoeas. index and arrhythmia index in a rodent model of conges- n Chronic congestive heart failure is the main risk factor for Cheyne–Stokes tive heart failure. Their findings suggest that statins may respiration and the severity of heart failure increases its incidence. However, the be an effective treatment for Cheyne–Stokes respiration. presence and severity of Cheyne–Stokes respiration ‘mirrors’ heart function and However, none of these medications has yet been recom- affects the overall prognosis. mended as a first-line treatment. n Although the pathogenesis of Cheyne–Stokes respiration is a very complex process involving multiple factors, the key point is the instability in the respiratory control

Ltd Prognosis Most available studies show a higher mortality in patients system occurring in patients with heart failure. with heart failure and Cheyne–Stokes respiration com- n The mainstay of treatment is to improve cardiac function, with continuous positive Healthcare pared to those without Cheyne–Stokes respiration. A airway pressure, adaptive servo ventilation and oxygen therapy as standards, and MA number of pathophysiological changes, such as sleep dis- bi-level positive airway pressure, acetazolamide and theophylline as options. 2015

© ruption, arousals, hypoxaemia-reoxygenation, hypercap-

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