Sleep-disordered breathing
Introduction
Erratic breathing during sleep in heart failure (HF) patients has been observed for centuries, with Cheyne–Stokes respiration (CSR) being the classic example.1,2 A rapid increase of knowledge in sleep medicine over the last few decades has identified a range of sleep-disordered breathing conditions, all of which have relevance to the cardiac patient. Sleep-disordered breathing (SDB) is a generic term used to cover the respiratory disturbances during sleep that include obstructive sleep apnoea (OSA), central sleep apnoea (CSA), CSR/periodic breathing, and obstructive and central hypoventilation. In adults, an apnoea is defined by 10 s of cessation in airflow; obstructive apnoeas are accompanied by respiratory effort; and in central events, effort is absent (Fig. 34.1). Hypopnoeas are partial events and are variously defined: most definitions include a reduction of more than 30% in respiratory airflow or thoracoabdominal excursion together with arterial desaturation of 2–4%, or more than 50% reduction in airflow without desaturation.
The syndrome of OSA is defined by the presence of more than 15 obstructive apnoeas and hyponoeas an hour; or more than 5 obstructive apnoeas and hyponoeas an hour associated with symptoms such as daytime sleepiness and fatigue, nocturnal choking, or unrefreshing sleep. The apnoea–hyponoea index (AHI) is the total number of these events per hour of sleep. Severe SDB is considered to be present if there are more than 30 apnoea and hyponoeas per hour. The respiratory disturbance index (RDI) is used to express the total number of respiratory events per hour of study time and therefore may differ from the AHI as any episodes of wakefulness during the monitoring period will be included in the RDI.
Sleep in heart failure
The prevalence of SDB has been examined in a variety of studies over the last decade (Table 34.1).3–9 Some studies are very small and the prevalence will vary according to whether results are derived from community screening or referrals to a sleep laboratory: subjects in the latter group are likely to have symptoms. More recent findings in optimally medically treated HF patients, however, suggest that SDB is present in around 50% of patients with chronic HF. In the most recent study, by Bitter et al.6 an AHI greater than 15 was found in 47% of patients with HF and normal left ventricular ejection fraction (LVEF). These results compare to a prevalence of obstructive apnoea syndrome in 4% of males and 2% of females in the general population.10 Previously it was assumed that SDB, particularly CSR, was a marker or epiphenomenon of endstage HF, but it is becoming clearer that SDB is found in patients with mild HF5 and is likely to contribute to functional cardiac decline through a range of mechanisms including hypoxaemia, increased sympathetic drive and oxidative stress.11 Treatment to control SDB is therefore an important potential management tool.
Table 34.1 Prevalence of sleep-disordered breathing in heart failure
Author, year | Number of patients | NYHA class | Male (%) | LVEF (%) | SDB severity (AHI) | OSA (%) | CSA (%) |
|---|---|---|---|---|---|---|---|
Lanfranchi, 2003 | 47 | I | 89 | 27(6) | 〉15/h | 11 | 55 |
Ferrier, 2005 | 53 | I–II | 77 | 34(9) | 〉10/h | 15 | 53 |
Javaheri, 2006 | 100 | II | 100 | 25(7) | 〉15/h | 37 | 12 |
Oldenburg, 2007 | 700 | 〉II | 80 | 28(7) | 〉15/h | 19 | 33 |
Schulz, 2007 | 203 | II, III | 75 | 28 | 〉10/h | 43 | 28 |
Vazir, 2007 | 55 | II | 100 | 31(10) | 〉15/h | 15 | 38 |
MacDonald, 2008 | 108 | 〉II | 85 | 20 | 〉15/h | 30 | 31 |
Bitter, 2009 | 244 | II–IV | 64 | 〉55 | 〉15/h | 24 | 23 |
AHI, apnoea–hyponoea index; CSA, central sleep apnoea; LVEF, left ventricular ejection fraction; OSA, obstructive sleep apnoea; SDB, sleep-disordered breathing.
Diagnosis of sleep-disordered breathing
Establishing the diagnosis of SDB almost always involves a sleep study to determine whether respiratory disturbances are present and to determine their nature, frequency, and pathophysiological consequences. It is often asserted that detailed polysomnography (assessment of ECG, electro-oculogram, and chin electromyogram to establish sleep stage and arousals, chest and abdominal effort sensors, airflow detection, oximetry, periodic limb and snoring monitoring) is the gold standard technique. However, the diagnosis can usually be secured by monitoring of respiratory variables such as pulse oximetry, airflow, respiratory effort, snoring, and position monitoring. Oximetry alone may establish the diagnosis in severe OSA and can be used to screen heart failure patients for SDB but cannot differentiate between obstructive and central sleep apnoeas. Further trials are in progress to establish the most effective method to screen patients including use of the simple ‘ApneaLink’ device (ResMed Co., Abingdon, UK) which detects airflow, and heart rate variation analysis from 24-h ECG monitoring.12 Clearly screening becomes more relevant if therapy is available. This is the case in OSA, but the management of CSA in HF remains controversial (see ‘Central sleep apnoea’, below).
In many patients, a mixture of obstructive and central apnoeas and hyponoeas is present. OSA is diagnosed if more than 50% of the events are obstructive and CSA diagnosed when more than 50% of the events are central.
Night-to-night variation in sleep-disordered breathing
In one study examining stable HF patients over four consecutive nights in the home, Vazir et al.13 showed that there was minimal change in the AHI, but around 40% of patients demonstrated a shift in the type of events either from OSA to CSA or vice versa. Remarkably, there is also within-night variation in some patients. Tkacova et al.14 carried out polysomnography in 12 stable patients with mean LVEF of 28.4% (±3.2%) NYHA class II or III, mean age 62.5 years. During the night, circulation time and periodic breathing cycle length increased, while transcutaneous Pco2 level fell. The changes were accompanied by a reduction in obstructive events as the night progressed and increase in central events. As discussed below, the increase in cycle length is likely to reflect worsening HF overnight, which in turn leads to a shift from OSA to CSA.
Obstructive sleep apnoea
Mechanisms
Obstructive apnoea occurs when the pharynx collapses during sleep, usually at nasopharyngeal, oropharyngeal, and/or hypopharyngeal levels. The obstruction is observed as pharyngeal dilator muscle tone is reduced with the onset of sleep. In addition, the supine posture favours airway collapse, and any obesity causing thickening of the neck adds to anatomical narrowing. In the recumbent position, fluid shift from the legs may increase pharyngeal oedema. Muscle tone is at its nadir in rapid eye movement (REM) sleep.
As a result of airway collapse, arterial oxygen saturation falls and the patient makes increasing respiratory efforts to overcome the obstruction. The pulmonary stretch receptors are stimulated, which causes disinhibition of central sympathetic outflow, thereby increasing heart rate. Arousal to a lighter stage of sleep terminates the apnoea but the associated cortical activity also causes a burst of sympathetic activity and loss of vagal tone. The postapnoeic period is thus characterized by a surge in sympathetic outflow and a brisk increase in blood pressure and heart rate. Once arousal has opened the airway, deeper sleep ensues, the pharynx collapses, and the cycle begins again.
Sleep apnoea can directly affect cardiac function. During the respiratory effort against the occluded airway there is a reduction in intrathoracic pressure. In turn, there is a consequent increase in left ventricular transmural pressure and therefore the afterload against which the left ventricle has to eject blood. Venous return is augmented, producing right ventricular distension which may shift the interventricular septum to the left so reducing left ventricular filling.
OSA may also have proinflammatory, oxidative stress and endothelial effects. Patients with OSA have higher plasma C-reactive protein (CRP) levels than controls15 and increased reactive oxygen species in neutrophils and moncytes.7 In OSA patients with ischaemic heart disease, raised levels of soluble circulating adhesion molecules and increased expression of CD15 and CD11c have been reported. Patients with OSA treated with continuous positive airways pressure support (CPAP) appear to have down-regulation of the expression of the adhesion molecules CD15 and CD11c in monocytes.16 Such changes suggest that OSA might be associated with the development of atherosclerosis, but as yet there is no clear evidence that it does. Hypoxaemia increases production of angiogenic promoters such as vascular endothelial growth factor (VEGF). In patients with OSA, VEGF level is proportional to the number of apnoeas and degree of nocturnal hypoxaemia,17 but again, no direct link has been demonstrated between OSA and angiogenesis.
Pathophysiological consequences
The pathophysiological consequences of sleep apnoea are outlined in Fig.34.2. In general, they can be divided into the effects of hypoxaemia, the impact of arousals including sympathetic hyperactivity and sleep fragmentation, and the effects on haemodynamics.18 In practice, the pathophysiological changes have combined consequences which are likely to converge to exacerbate the progression of cardiac failure and increase mortality.
A prospective epidemiological study has shown that OSA is an independent risk factor for the development of systemic hypertension, and nocturnal blood pressure in patients with hypertension who also have OSA is higher than those without SDB.19 In patients with HF, elevated daytime blood pressure is increased in proportion to the AHI (in other words, daytime blood pressure is increased in relation to the severity of OSA). In a related effect, OSA diminishes or prevents the usual fall in heart rate and blood pressure that occurs during sleep, and heightened sympathetic tone may predispose individuals to arrhythmia.
Each deep inspiratory effort to open the occluded airway during an apnoea can be associated with very marked swings in intrathoracic pressure. Negative intrathoracic pressures of more than 60 cmH2O have been recorded. These frequent pressure swings are associated with an increase in afterload and large falls in stroke volume can be seen as a consequence. The repetitive falls in stroke volume occur on a background of arterial hypoxaemia. The repetitive stimuli every night could play a role in myocyte and contractile dysfunction setting up a progressive cycle of cardiac decline.
The presence of OSA has an impact on survival in patients with HF. Kasai et al.20 studied 88 patients with HF (NYHA II or III, LVEF 36%) and moderate to severe OSA to establish outcome in those who either were untreated, received CPAP therapy, or were provided with CPAP but did not comply. During an average follow-up period of 25 months, 44.3% of patients died or were hospitalized. On multivariate analysis, the risk of death and hospitalization was increased in the untreated group (hazard ratio 2.03, 95%CI 1.07–3.68, p = 0.030) and in the poorly compliant CPAP group (hazard ratio 4.02, 95 CI 1.33–12.3, p = 0.014). However, this was a nonrandomized observational study. The results are supported by other work, although Roebuck et al.21 showed no impact of CPAP on survival in HF patients with OSA. Compliance with CPAP was not documented in the latter study, however, so it is possible that patients in the treatment limb did not receive effective CPAP. Further randomized studies looking at the impact of CPAP are likely to be unethical: most patients with OSA are symptomatic, particularly with daytime sleepiness, which CPAP consistently addresses, and it would be unethical to randomize them to no treatment, particularly as they are not allowed to drive without CPAP treatment.
Treatment of obstructive sleep apnoea in heart failure
Management strategies include optimization of therapy for HF, weight loss, positional modification during sleep, positive pressure ventilatory devices, mandibular advancement splints, and oxygen therapy. While optimization of cardiac function and achieving ideal body weight are sensible, the burden of evidence concerns CPAP therapy. There are few data on the use of the mandibular advancement splint in HF patients with OSA.
Impact of treatment of heart failure
Interventions to improve cardiac function are likely to prove beneficial by decreasing both upper airway oedema and pulmonary oedema, thereby stabilizing ventilation. It was previously thought that β-blockers could predispose individuals with HF to OSA, but this has not been borne out in treatment comparison studies.22 A preliminary report by Garrigue and coworkers23 suggested that atrial overdrive pacing at a rate of 15 beats/min faster than mean nocturnal heart rate reduced AHI in a group of patients with both OSA and CSA. While an impact on CSA is plausible via an improvement in cardiac output leading to a decrease in heart–lung circulation time and left ventricular filling pressure, the effect on obstructive events is more difficult to explain. Subsequent work has not, however, confirmed the finding and thus the role of atrial overdrive pacing has not been convincingly demonstrated.
Of more relevance is cardiac resynchronization therapy (CRT). While again this might be expected to be more effective in HF patients with CSA, Stanchina et al.24 have examined the impact of CRT in HF patients with OSA. They found that mean ejection fraction increased from 22 (±1.7)% to 33.6 (±2.0)% and AHI fell from 40.9 (±6.4) to 29.5 (±5.9) with CRT. As AHI still remained abnormal, it is not surprisingly that there was no improvement in sleep architecture or sleep-related symptoms.
Given that upper airway anatomy and body habitus contributes to OSA, cardiac transplantation might be expected not to reduce this component of SDB compared to potential beneficial effects on CSA. This seems indeed to be the case, and some transplant patients may in fact develop OSA.
Positive airway pressure therapy
In an early uncontrolled study of the effects of CPAP on patients with dilated cardiomyopathy and OSA, CPAP therapy for a month increased LVEF from 37% to 49% and breathlessness was reduced.25 The improvements were lost when CPAP was withdrawn. In a randomized study of 24 patients with mean LVEF less than 45% and AHI greater than 20, CPAP lowered daytime heart rate and systolic blood pressure and increased LVEF by 9% over 30 days compared to no change in a matched control group who did not receive CPAP.26 In a further randomized study in congestive HF (CHF) patients with OSA, CPAP improved LVEF more modestly (5%) and peak exercise capacity did not change. There was a reduction in daytime sleepiness.27 More recent outcome data suggests that there is a decrease in mortality in HF patients with OSA treated with CPAP compared to those who did not receive CPAP.20 It is important to stress, however, that the patients were not randomized, so the two treatment groups may represent different populations. As outlined above, it would now be problematic ethically to have a control group of patients with proven OSA randomized to no CPAP therapy.
Central sleep apnoea
Mechanisms
CSA and CSR represent forms of periodic breathing. In contrast to OSA, CSA/CSR arises as a consequence of HF itself. Pulmonary congestion and hypoxaemia stimulate receptors within the lung that cause hyperventilation which in turn lead to low arterial CO2 levels. Lung congestion may be increased on lying flat at night as venous return from the limbs increases. If Pco2 falls below the threshold required to stimulate breathing, a central apnoea occurs and continues until Pco2 rises above the apnoeic threshold. Termination of the apnoea may be accompanied by arousal which stimulates breathing and drives down CO2 again, leading to a self-perpetuating oscillation between apnoea and hyperpnoea. Prolonged circulation time delays information on arterial blood gas tensions from the lungs reaching the central chemoreceptors in particular, and thereby adds to periodicity such that the length of the ventilatory phase is inversely proportional to cardiac output.11
Pathophysiological consequences
Like OSA, CSA is associated with cyclical hypoxaemia, arousal from sleep and sympathetic activation. Passive airway collapse may occur at the end of a central event. Risk factors for the development of CSA/CSR are male sex (perhaps because of higher baseline chemosensitivity in males), age, and the presence of atrial fibrillation. It used to be thought that CSA/CSR was a paraphenomenon and simply represented the presence of severe HF. This is unlikely to be the case as new prevalence studies have shown a high prevalence of CSA in patients with mild HF.5,6 Importantly, patients with HF and CSA/CSR have a worse prognosis than those without this form of SDB.28
Treatment
Impact of treatment for heart failure on central sleep apnoea
Therapies that improve cardiac function should also decrease CSA/CSR. Use of angiotensin-converting enzyme (ACE) inhibitor therapy and diuretic therapy to reduce left ventricular filling pressure can produce a decrease in AHI. Vazir et al.29 showed that an left ventricular assist device (LVAD) reduced CSA/CSR. Therefore steps to optimize cardiac function should always be taken first.
Other therapies
A short term trial of aminophylline produced a reduction in CSA but did not change left or right ventricular function or quality of life.30 Oxygen therapy at night corrects apnoea-related hypoxaemia and decreases nocturnal noradrenaline level while increasing exercise capacity.31 However, over a month there was no impact on cardiac function or quality of life.32 Acetazolamide may reduce apnoeas short term but long-term effects have not been examined.
From a theoretical viewpoint, increasing Pco2 by either inhaling CO2 or rebreathing dead space might be expected to stabilize periodic breathing by raising Pco2 above the apnoeic threshold. Simple inhalation of CO2 does not seem effective: while it may reduce apnoeas, cortical arousals are increased.33 Similarly, breathing dead space has been shown to reduce central apnoeas but the benefit was offset by an increased work of breathing.34 Notwithstanding concerns on the safety of asking patients to breathe CO2 overnight, Mebrate et al.35 have shown in an experimental model that targeted short-burst CO2 in a small portion of the ventilatory cycle may stabilize ventilation, but this remains a highly exploratory approach.
Positive pressure therapy
Following the success of CPAP therapy in the management of OSA in HF patients, CPAP use has been extended to patients with CSA. However, the mechanisms of OSA and CSA are clearly different and there is no equivalent respiratory endpoint (opening the airway) to titrate therapy against. Furthermore, CPAP therapy can mildly reduce Pco2 which might destabilize breathing further. Despite these physiological considerations, initial short-term uncontrolled trials suggested benefit from CPAP in treating CSA in terms of control of SDB and a reduction in ventricular ectopics. In a randomized study of 20 patients with HF and CSA, those who complied with CPAP therapy had a significant reduction in the combined rate of mortality/transplantation over 5 years.36 However, the improved outcome disappeared when outcome was analysed on an intention-to-treat basis.
As a consequence of this work, the Canadian Positive Airway Pressure Trial for patients with congestive cardiac failure and CSA (CANPAP)14 recruited 258 patients randomized to receive CPAP or usual therapy. In the patients treated with CPAP, mean nocturnal arterial oxygen saturation increased and there was a small improvement in LVEF. There was an early excess of deaths in the CPAP treated limb, but after 2 years the primary endpoint of combined mortality and transplantation was identical in CPAP and control groups. Recruitment and event rate was slowed by advances in medical and device therapy as the trial progressed, leaving it underpowered, and so the trial was terminated prematurely.37 A post-hoc analysis suggested that there might be improved survival in patients in whom apnoeas/hyponoeas and CSR was suppressed.38 This might indicate that therapies better able to suppress SDB may be more effective.
Adaptive servoventilation (ASV) is a form of ventilation that has been designed to smooth out periodic breathing in CSA/CSR by providing ventilatory support during apnoeic periods and reducing the support as spontaneous ventilation begins again. Over a relatively short period, breathing is captured and periodicity removed. As a result, arterial Pco2 is stabilized, in turn stabilizing breathing further (Fig. 34.3) Positive pressure is provided in expiration to maintain upper airway patency and control any mixed or obstructive respiratory events.
Small studies have shown good control of AHI: in a one-night cross-over study ASV was more effective at controlling AHI, reducing arousals, and normalizing sleep quality than oxygen therapy, CPAP, or bilevel noninvasive ventilation.39 In addition, ASV appears to be better tolerated by patients than CPAP and so more likely to be effective long term.40 In a ‘real world’ study, HF patients with CSA/CSR who accepted ASV had a significant improvement in LVEF compared to those who did not receive ASV for 6 months.41 Conversely, Pepperell et al.42 showed improvement in sleep-related symptoms and nocturnal sympathetic measures but no change in ejection fraction. The multicentre Serve HF trial is now examining the effects on ASV in HF patients with predominant CSA/CSR on hard clinical endpoints including long-term cardiac and all-cause mortality, and hospital admissions. Other studies are planned looking at positive pressure therapy in HF patients with combined OSA and CSA.
Heart failure in neuromuscular disease
It should not be forgotten that some forms of inherited neuromuscular disease have associated cardiac muscle involvement. Cardiomyopathy is almost inevitable in Duchenne muscular dystrophy, and cardiac involvement is seen in Becker and Emery Dreifuss muscular dystrophies, myotonic dystrophy, LGMD 1B, LGMD 1D, LGMD2C-2 sarcoglycanopathy variants of limb girdle muscular dystrophy, and some other myopathies such as acid maltase deficiency. Many of these patients also have respiratory muscle weakness resulting in ventilatory failure.
In some groups the introduction of noninvasive ventilation to control nocturnal hypoventilation has increased survival and reduced respiratory complications so that cardiomyopathy becomes a key prognostic factor. A combination of noninvasive ventilation and optimal cardiac failure therapy means that many patients with Duchenne muscular dystrophy are now living into their 30s. Anticipation of problems with serial monitoring by yearly ECG and echocardiogram is now part of the standard of care in these conditions as the previous nihilistic approach to care is now unjustified.43
Duboc44 has carried out a randomized controlled trial of perindopril in Duchenne patients aged between 9.5 and 13 years (LVEF 〉55%) for 3 years, after which both perindopril and placebo limbs received open label perindopril 2–4 mg/day as tolerated for a further 2 years. LVEF was similar in both groups after 3 years, but after 5 years a single patient in the phase I perindopril group had an LVEF less than 45%, whereas eight patients had LVEF below 45% in the phase I placebo group (p = 0.02). Currently a trial of combined prophylactic ACE inhibitor and β-blocker is in progress in children with Duchenne muscular dystrophy.
Clinical features and implications
It is important to realize that the symptoms of OSA and CSA may differ. While OSA patients are classically sleepy as quantified by Epworth sleepiness score (ESS),45 patients with CSA (and some HF patients with OSA) do not routinely complain of sleepiness. The ESS is usually within the normal range (〈10). Snoring, choking episodes and struggling to breathe are noted by partners of patents with OSA but not those with CSA. The latter may, however, complain of poor quality, fragmented sleep together with tiredness or fatigue. In addition, despite the lack of subjective sleepiness, objective measures of vigilance are reduced, and daytime activity, as measured by actigraphy watches, is reduced in HF patients with all forms of SDB compared to those with no SDB.46
Practicalities of assessment in the clinic and therapy
The lack of typical symptoms raises the question of how to identify HF patients with SDB in the clinic. A story of snoring, witnessed apnoea, and daytime sleepiness should be specifically asked for as the symptoms may be present in some, particularly those with higher BMI. SDB occurs in up to three-quarters of CHF patients with chronic atrial fibrillation (AF),47 so there should be a low threshold for asking about symptoms and carrying out a sleep study in this group. As the presence of SDB cannot be easily predicted in others, a variety of screening mechanisms is being investigated. Screening is, of course, only justified where effective treatment is available for the condition detected. At present, there is good evidence in favour of treating OSA in CHF, but until Serve HF and other trials report, the best management of CSA/CSR is less clear. Screening methods which can be used in the home include oximetry, analysis of heart rate variation, and apnoea detection.
CPAP treatment is best started by experienced teams and a good link between cardiology departments and sleep departments is highly recommended. In patients with labile HF and poor cardiac output, initiating CPAP is more safely done with the patient in hospital with haemodynamic monitoring. In stable CHF patients with OSA, outpatient set-up is usually effective as long as there is careful explanation of the anticipated benefit, the importance of fitting of mask interface, and support in the home.48 Autoset variable pressure devices can be used to determine the correct pressure setting overnight, but for long-term use, fixed-level standard CPAP machines are usually sufficient. Continued input from the CPAP team to maintain compliance and adherence is helpful. Patients with HF often have other comorbidities. In those with additional severe chronic obstructive pulmonary disease (COPD) or obesity resulting in nocturnal hypoventilation, obstructive hypopnoeas or even obesity–hypoventilation syndrome and daytime hypercapnia, noninvasive ventilation is likely to be preferable to autoset devices.
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