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CSA in chronic heart failure

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Optimising HF therapy

The impairment of le ventricular function is a major factor predisposing to the development of central apnoeas and periodic breathing. Volume overload stimulates lung parenchymal aerents and induces ventilatory overshoot (see chapter 3.2 ‘Pathophysiology of central sleep apnoea’). Thus, optimisation of cardiac function represents a causal and primary therapeutic approach to patients with HF and central disturbances. Peripheral oedema and pulmonary congestion should be avoided or treated with cardiotropic agents, diuretics or haemodialysis. Cardiac interventions or surgery may improve oxygenation of the heart muscle.

There is limited evidence from non-randomised, small-sized trials on the use of cardiotropic drugs to improve central breathing disturbances in HF. Angiotensinconverting enzyme inhibitors, beta-blockers, and individually selected combinations may improve le ventricular function, central breathing disturbances, subjective sleep quality and objective PSG parameters. In addition, a small study found a signiﬁcant improvement of central disturbances under active cardiac resynchronisation therapy. The eect was signiﬁcantly correlated with the reduction of mitral regurgitation.

If treatment of the underlying cardiac disease does not suciently reduce central breathing disturbances, symptomatic therapies can be considered. Data from cohorts and longitudinal studies suggest that CSA is a marker or cause of poor outcome, although evidence from prospective randomised controlled trials (RCTs) on the therapeutic inﬂuence on survival is limited. Therefore, the decision to treat also depends on clinical symptoms, such as quality of life or exercise performance.

These symptomatic approaches interfere with dierent components of the loop gain (see chapter 3.2 ‘Pathophysiology of central sleep apnoea’). Oxygen supply may interfere with the peripheral chemosensitivity and the hypoxic ventilatory response (HVR); carbon dioxide (CO2) with the hypercapnic ventilatory response (HCVR) and the CO2 reserve; drugs inﬂuence arousals, respiratory drive, plant gain and controller gain. These aspects will be addressed in the following chapters in this section ‘Management of central sleep apnoea’, while the focus here will be on the dierent positive pressure applications.

PAP treatment

CPAP or automatic PAP (APAP) is the gold standard of the treatment of OSA. BPAP applies two dierent but ﬁxed pressure levels during inspiration and expiration. It can be used in spontaneous mode in OSA therapy or with back-up mandatory breaths in hypercapnic failure. ASV represents the most speciﬁc approach to patients with CSA or periodic breathing, as it counteracts the typical breathing patterns and intervenes with apnoeas.

Patients may present with pure central breathing disturbances, but also with combined OSA and CSA. Thus, in addition to ventilatory support, stabilisation of the upper airways may be required in individual HF patients. The heterogeneity of the underlying pathophysiology between the individuals requires the clinician to choose one of the dierent PAP options and set the pressure levels individually.

Eect of PAP therapies in HF and central breathing disturbances

PAP stabilises peripheral airways, improves ventilation –perfusion mismatches, and improves gas exchange. It also enlarges the FRC, which reduces the variation of the gas proportions in the alveoli. PAP also mechanically inﬂuences the interstitial ﬂuid accumulation and cardiac pre- and aerload.

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There is convincing evidence that CPAP does not generally normalise central breathing disturbances in HF, but reduces them by a mean of 50%. This is associated with improvements of oxygen saturation and (inconsistently) LVEF. The CANPAP trial (Canadian trial of CPAP for patients with CSA and HF) achieved this eect with pressure levels of 8–12 cmH2O.

The question arises of whether dierent phenotypes of central breathing disturbances may be responsible for the inconsistent response to CPAP. Actually, several clinical and pathophysiological factors seem to inﬂuence outcome in HF patients with CSA. Low LVEF and high hypoxic burden indicate reduced survival. Interestingly, increased chemosensitivity (as measured by HVR or HCVR), the presence of an exercise oscillatory pattern of the ventilation, and higher amounts of periodic breathing are associated with higher mortality. These factors indicate that the instability of respiration (high loop gain) is a marker of poor outcome and may help in deﬁning phenotypes of CSA. It has been shown that the loop gain was markedly higher in patients who did not respond suciently to CPAP regarding their CSA. A low loop gain is associated with better reduction of breathing disturbances, especially periodic breathing, in HF patients. Post hoc analyses of the CANPAP data suggest that CPAP responders have a survival beneﬁt compared to nonresponders. However, it is not clear whether CPAP actually improves survival or if the better response to CPAP characterises a phenotype of CSA in HF with better survival.

At present, it is dicult to predict the response to PAP treatment in an individual patient before initiation. The 50% reduction of central disturbances, the almost complete resolution of any additional upper airway obstruction, and the survival beneﬁt in responders justify a CPAP trial in HF with central or combined obstructive and central disturbances.

Data on the use of BPAP treatment in HF with CSA are scarce. A prospective RCT showed that BPAP in spontaneous/timed mode suciently reduced breathing disturbances in the ﬁrst night, but this eect was abolished over 6 weeks. Therefore, BPAP cannot be recommended at this stage. It can even aggravate instability because of its inevitable mandatory ventilation. In addition, there is limited and controversial evidence on the use of APAP in HF patients with CSA, so that it too cannot be recommended.

ASV

The limitations of CPAP and BPAP indicate the need for more eective and more speciﬁc PAP options, interfering with the underlying pathophysiology of CSA and periodic breathing. ASV has been designed with the following three aims:

• To counterbalance the periodic breathing pattern in HF

• To stabilise the upper airways in case of accompanying OSA

• To avoid central apnoeas

The term ASV summarises devices from several manufacturers, which commonly integrate the following:

• An anticyclical variation of pressure support during inspiration

• A variable end-expiratory pressure

• The optional application of mandatory breaths

The devices measure patient ﬂow or V′E based on a breath-by-breath or intrabreath analysis. In cases of high patient ﬂow, the devices reduce pressure support;

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1a)

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they increase it during hypoventilation. Therefore, they avoid ventilatory over- and undershoot, reduce excessive swings of hypoxia and hypercapnia, reduce the loop gain, and thus stabilise ventilation (ﬁgure 2).

The most recent versions of the ASV devices allow for variable adjustment of the end-expiratory pressure according to the prevailing upper airway obstruction. They react like APAP. The ﬁrst generations applied a minimal inspiratory pressure support of 3 cmH2O, even if there was no need for mechanical ventilation. This may have contributed to hyperventilation, hypocapnia and increase of the loop gain in some patients. The new versions allow for zero pressure support in periods of spontaneous hyperventilation.

ASV is the second-line PAP therapy in HF patients and can be considered when CPAP fails to resolve the central disturbances. However, in each patient, the previous CPAP

2 3 4

5 6

7 8

10 11 12 13 14

15 16

1 2

3 4 5 6 7 8

9 10 11 12 13 14

15 16 17

18 19

Figure 2. a) Measurements from a patient with periodic breathing. b) Measurements from the same patient under ASV therapy, showing that pressure support increases and decreases anticyclically to the patient’s ﬂow and eort: during hypoventilation, the pressure support is increased; during hyperventilation, it is decreased. Lines 1 and 2: EEG; 3 and 4: EOG; 5: EMG; 6: leg right; 7: leg le; 8: microphone; 9: nasal ﬂow; 10: thorax eort; 11: abdomen eort; 12: eort sum; 13: oxygen saturation measured by pulse oximetry (S IPAP/EPAP swings; 17: leakage; 18: heart rate; 19: body position.

206

); 14: IPAP; 15: EPAP; 16:

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trial oers important information about the pressure level required to overcome any concomitant upper airway obstruction. This may help in deﬁning the range of the expiratory pressure on the ASV device.

Ecacy of ASV

Several RCTs have proven that ASV is the most eective option to overcome central breathing disturbances, especially periodic breathing, in HF patients. One trial showed that ASV was superior to CPAP, BPAP and oxygen over the short term. This was conﬁrmed in groups of patients with severely reduced LVEF and in studies over mid- to long-term periods. ASV additionally improved parameters of le ventricular function, daytime performance, quality of life, sleep and adherence. The clinical ecacy of ASV is underlined by its inﬂuence on major pathophysiological parameters. Another trial demonstrated a reduction of HCVR, which is a marker of chemosensitivity, instability of breathing and prognosis.

Available evidence demonstrates that ASV eectively stabilises upper airway obstruction and counterbalances central breathing disturbances in various clinical entities, including patients with coexisting CSA and OSA, treatment-emergent CSA (TECSA) and opioidinduced CSA (see the following chapters in this section ‘Management of central sleep apnoea’). This is accompanied by improvement of biomarkers and patient-relevant outcome measures and is based on the stabilisation of the increased loop gain.

Impact on prognosis

There are controversial results on the beneﬁt or harm of ASV in patients with HF. The SERVE-HF trial (ASV for CSA in systolic HF) compared ASV plus optimal conventional therapy with optimal conventional therapy alone. It included chronic HF patients (LVEF ≤45%) with predominant CSA. The composite primary cardiac outcome parameter did not dier between the treatment groups, but the number of events of death from any cause and cardiovascular deaths was signiﬁcantly higher in the ASV group (secondary outcome parameters). Post hoc analyses limited the risk of harm to ‘cardiovascular death without previous hospital admission for worsening of HF or life-saving intervention’ and ‘hospital admission for worsening of HF’ in patients with LVEF <30% and to ‘hospital admission for worsening of HF’ in patients with CSR for >50% of the recording time. However, ASV is currently restricted for patients fulﬁlling the inclusion criteria of SERVE-HF (predominant CSA in HF with LVEF <45%).

The publication of SERVE-HF has raised critical questions on the design and performance of the trial. 23% of participants changed treatment arm and thus violated the randomisation. The treatment adherence was extremely low (27% <1 h·day−1, 40% <3 h·day−1). Data on the major inclusion criterion LVEF were missing in 19%.

The majority of fatal events in SERVE-HF were due to sudden cardiac death and not to HF decompensation, and did not happen during the night. Some factors have been discussed that may possibly have contributed to the mortality. For example, patients with severely reduced LVEF face a high risk of malignant arrhythmias. This may have been increased by two aspects: 1) there was an imbalance between the treatment groups regarding antiarrhythmic treatment and, as antiarrhythmics have a pro-arrhythmic eect, their higher usage in the ASV group may have propagated sudden cardiac death; 2) the ﬁrst-generation ASV device used in the trial delivered a minimal pressure support of 3 cmH2O and this unnecessary pressure support might have aggravated hyperventilation and metabolic alkalosis, and increased critical

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arrhythmias. In contrast, it has been considered that CSR may have a compensatory eect in HF and the resolution of CSR under ASV may erase this beneﬁcial eect. However, these arguments do not seem explanatory as the fatal events did not happen during sleep and patients did not die from HF decompensation.

These open questions require additional data. The results of the ADVENT-HF trial (eect of ASV on survival and cardiovascular hospital admissions in patients with HF and sleep apnoea), the second large multicentre prospective RCT for ASV, have been preliminarily published in August 2022. The study investigates the eect of ASV in HF patients with CSA or OSA. Although the study had to be terminated prematurely due to the inﬂuences of the coronavirus disease 2019 (COVID-19) pandemic and the Philips recall, the study did not show any harm of the ASV therapy in the intention-to-treat analysis. The hazard ratio for ASV in CSA patients was 0.75 in favour of ASV, which was not signiﬁcant but fulﬁlled exactly the presumptions of the power calculation. Further analyses, e.g. on quality of life parameters, are still to be expected.

The results of ADVENT-HF are in line with data from other prospective studies, cohorts and databases on the ecacy of ASV. They showed signiﬁcantly better survival in HF patients with good ASV adherence compared to those with poor adherence over 1 year (hazard ratio 0.53, 95% CI 0.27–0.99). This was conﬁrmed in prospective cohorts of patients aer stabilisation of decompensated HF. Mortality signiﬁcantly improved in ASV-treated patients (hazard ratio 0.32, 95% CI 0.12–0.84; p=0.02). In addition to these ﬁndings in HF with reduced LVEF, some prospective studies described superiority of ASV on cardiovascular end-points in the subgroup of patients with HF and preserved ejection fraction.

These aspects lead to the concept of a personalised approach. There is growing evidence of a heterogeneity of phenotypes of CSA, also presenting with dierent prognosis. This obviously suggests that not one treatment option is optimal for every patient. The FACE study, a European, multicentre, prospective, observational cohort trial, presented real-world data of unselected HF patients. It focused on a more dierentiated analysis of the treatment eects and limitations in subgroups of HF patients with CSA/CSR. They identiﬁed six discrete patient clusters characterised by variations in LVEF, OSA or CSA, age, comorbidities and ASV acceptance. The 3-month rate of primary outcome events was signiﬁcantly higher in the cluster characterised by male sex, low LVEF, severe HF and predominant CSA. The cluster allocation was more relevant for outcome than speciﬁc treatments.

Based on these considerations, an ERS task force proposed a therapeutic approach to patients with CSA with and without coexisting OSA presenting with various clinical entities and symptoms and dierent severity of HF. For patients with idiopathic CSA and those not improving under conventional treatment of any underlying disease, a CPAP trial is indicated. If this fails, ASV is the next step in HF patients with predominant OSA and in CSA patients with LVEF >45% or preserved ejection fraction. The current ocial restrictions do not allow the recommendation of ASV for HF patients with LVEF ≤45% and predominant central breathing disturbances. In daily practice, the group of patients fulﬁlling the inclusion criteria of the SERVE-HF trial is small. Dierent studies with cardiac and pulmonary populations showed that only 10% of the ASV-treated patients would have to withdraw from ASV therapy. Moreover, the new data from ADVENT-HF should urge reconsideration of the restrictions. Other treatment options such as BPAP in spontaneous mode, CO2 supply or drugs cannot be recommended due to limited available data.

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Further reading

• Arzt M, et al. (2007). Suppression of central sleep apnea by continuous positive airway

pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP). Circulation; 115: 3173–3180.

• Bradley TD, et al. (2005). Continuous positive airway pressure for central sleep apnea and

heart failure. N Engl J Med; 353: 2025–2033.

• Cowie MR, et al. (2015). Adaptive servo-ventilation for central sleep apnea in systolic heart

failure. N Engl J Med; 373: 1095–1105.

• Dellweg D, et al. (2013). Randomized controlled trial of noninvasive positive pressure

ventilation (NPPV) versus servoventilation in patients with CPAP-induced central sleep apnea (complex sleep apnea). Sleep; 36: 1163–1171.

• Javaheri S, et al. (2014a). Positive airway pressure therapy with adaptive servoventilation.

Part 1: operational algorithms. Chest; 146: 514–523.

• Javaheri S, et al. (2014b). Clinical applications of adaptive servoventilation devices. Part 2.

Chest; 146: 858–868.

• Javaheri S, et al. (2016). SERVE-HF: more questions than answers. Chest; 149: 900–904.

• Khayat R, et al. (2015). Sleep disordered breathing and post-discharge mortality in patients

with acute heart failure. Eur Heart J; 36: 1463–1469.

• Perger E, et al. (2019). Predictors of 1-year compliance with adaptive servoventilation in

patients with heart failure and sleep disordered breathing: preliminary data from the ADVENTHF trial. Eur Respir J; 53: 1801626.

• Randerath W, et al. (2017a). Deﬁnition, discrimination, diagnosis and treatment of central

breathing disturbances during sleep. Eur Respir J; 49: 1600959.

• Randerath W, et al. (2017b). Adaptive servoventilation in clinical practice: beyond SERVE-HF?

ERJ Open Res; 3: 00078-2017.

• Randerath W, et al. (2019). Central sleep apnoea and periodic breathing in heart failure:

prognostic signiﬁcance and treatment options. Eur Respir Rev; 28: 190084.

• Sands SA, et al. (2011). Loop gain as a means to predict a positive airway pressure suppression

of Cheyne–Stokes respiration in patients with heart failure. Am J Respir Crit Care Med; 184: 1067–1075.

• Sharma BK, et al. (2012). Adaptive servoventilation for treatment of sleep-disordered breathing

in heart failure: a systematic review and meta-analysis. Chest; 142: 1211–1221.

• Tamisier R, et al. (2022). Adaptive servo ventilation for sleep apnoea in heart failure: the FACE

study 3-month data. Thorax; 77: 178–185.

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adaptive servo ventilation in patients with opioid-induced sleep disordered breathing

Shahrokh Javaheri

Among the many causes of CSA, medication-induced CSA is one of the six categories of CSA noted in the ICSD third edition. Among the medications causing CSA, opioids are prime examples and they have been studied extensively. Notably, detoxiﬁcation eliminates CSA. The importance of the association lies in the fact that many individuals using opioids are found dead in bed with no cause found at autopsy, except opioids and some other drugs in the blood. It is generally assumed that a terminal apnoea is the cause of death.

Although, in general, CSA is a rare PSG ﬁnding, CSA is highly prevalent in opioid users and sometimes quite profound. The central apnoeas induced by opioids are of variable duration (short and prolonged), with a variable number of skipped breaths, amidst an ataxic pattern of breathing (ﬁgure 1a). This pattern is somewhat analogous to Mobitz type 2, where P waves are not transmitted through the conduction system, with variable dropped beats, and is in contrast to that of CSR, in which apnoeas are of the same duration and the pattern is not ataxic (ﬁgure 1b).

Reviewing the combined data of ﬁve studies and incorporating a total of 436 patients on opioids, data from Chowdhuri et al. (2017) showed that the prevalence of mild CSA (central apnoea index (CAI) ≥5 events·h−1), moderate CSA (CAI ≥15 events·h−1) and severe CSA (CAI ≥30 events·h−1) was 35%, 20% and 10%, respectively (table 1 and ﬁgure 2).

Aside from detoxiﬁcation, there are multiple options for treatment of CSA associated with opioids. However, treatment with PAP devices is the focus of this chapter.

Key points

• Both central and obstructive disordered breathing are prevalent in opioid users.

• All attempts should be made to withdraw the opioids, as detoxiﬁcation eliminates disordered breathing.

• ASV devices, when used intelligently, prove to be quite eective in treating opioid-induced SDB.

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Flow

Abdomen

Chest

CSA OSA CSACSACSA OSAHypopnoea Hypopnoea

Flow

Abdomen

Chest

Prevalence %

Mild Moderate Severe

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Figure 1. 5-min epochs of PSG traces. a) Typical ataxic breathing with CSA associated with opioids. Traces in stage N2, in a patient using opioids chronically, showing CSA and obstructive apnoeas/hypopnoeas. The pattern is ataxic and central apnoeas are of variable duration. b) CSR in HF. Traces in stage S2, in a patient with HF and reduced le ventricular ejection fraction, showing CSA. Note that in CSR, central apnoeas are of the same duration and the pattern of breathing is not ataxic. Flow measured by a pressure transducer, chest and abdomen eorts by ribcage and abdomen respiratory inductance plethysmography.

Table 1. Prevalence of CSA in ﬁve large studies

First author, year

Patients

on opioids CAI events·h

Mogri, 2009 98 43 NR NR Webster, 2008 147 48 34 21 Wang, 2007 50 17 NR 1 Sharkey, 2010 71 23 10 NR Farney, 2013 70 21 14 6 Total 436 152/436 (35%) 58/288 (20%) 28/267 (10%)

Data are presented as absolute numbers (n) unless otherwise stated. NR: not reported. Data from Chowdhuri et al. (2017).

Figure 2. Prevalence of CSA in the ﬁve large studies detailed in table 1. Mild: CAI ≥5 events·h−1; moderate: CAI ≥15 events·h−1; severe: CAI ≥30 events·h−1.

−1

≥5 ≥15 ≥30

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CPAP

In general, CPAP devices have proven ineective in eliminating CSA associated with opioids. Farney et al. (2008) reported one of the earliest cases of three patients who developed opioid-induced CSA that was unresponsive to CPAP. Allam et al. (2007) undertook a retrospective study of 100 patients who failed conventional CPAP therapy for various types of CSA, including opioids. In another study involving 20 patients on long-term opioids, Javaheri et al. (2008) showed that CPAP use both acutely and chronically for several weeks failed to improve CSA. These patients had severe OSA and CSA, typical PSG ﬁndings with opioid-induced SDB (ﬁgure 1a). The baseline AHI was 61 events per h of sleep and the CAI was 32 events·h−1. During overnight CPAP titration, AHI decreased to 34 events·h−1, as obstructive events were eliminated, but CAI remained elevated (20 events·h−1). Nine of the 20 patients used CPAP for several weeks and were quite adherent when a second titration was performed. In these nine patients, during diagnostic PSG, AHI was 45 events·h−1 and CAI was 20 events·h−1. AHI values decreased to 34 and 33 events·h−1 during the ﬁrst and second CPAP studies. Respective values for CAI were 20 and 19 events·h−1, demonstrating CPAP ineectiveness both acutely (CPAP 1) and with long-term CPAP use (CPAP 2). As will be discussed later in this chapter, ASV proved quite eective in eliminating CSA as well as OSA.

Bilevel devices

From a physiological point of view, bilevel devices could make CSA worse. This is because with bilevel devices, alveolar ventilation is increased, depending on the inspiratory pressure support (the dierence between inspiratory pressure and end-expiratory pressure). The higher the inspiratory pressure support, the higher the induced alveolar ventilation. Consequently, P more central apnoeas ensue. Guilleminault et al. (2010) found, in a study of patients

is lowered; if it drops below the apnoeic threshold P

aCO

with OSA and on chronic opioids who developed CPAP-emergent CSA (severe OSA of AHI 44 events·h−1 and CAI 0.6 events·h−1), when they were titrated with BPAP (mean IPAP 17 cmH2O, EPAP 12 cmH2O) the mean CAI increased from 0.6 to 12 events·h−1. As expected, with BPAP with a backup rate, CAI decreased (mean CAI 2 events·h−1).

ASV

ASV is the treatment of choice for mixed OSA and CSA of various causes including opioids. The algorithm of ASV devices varies depending on the manufacturer. In general, however, the devices use a breath-by-breath algorithm to analyse the ventilatory status of the patient. With this platform, a dynamic anticyclic inspiratory pressure support is applied when the patient hypoventilates leading to hypopnoea or apnoea, and a sloughing o during the hyperventilation that usually follows these disordered breathing events. In addition, ASV devices have a backup rate algorithm that imposes a mandatory breath to abort any impending apnoea. The new-generation ASV devices apply an autoPAP algorithm to eliminate obstructive events, an algorithm similar to automatic pressure (APAP) devices.

ASV devices have been used extensively for treatment of opioid-induced CSA. An early study by Javaheri et al. (2011) showed the ecacy of an ASV device and its operation to eliminate SDB. Later, in a long-term clinical study, in 20 patients with mixed obstructive and central SDB secondary to chronic opioid therapy, Javaheri et al. (2014c) used a stepwise titration protocol with PAP devices. CPAP proved eective in eliminating obstructive events but ineective in reducing central apnoeas at initial titration and a few weeks later, despite all patients being compliant. In these 20 patients, the mean CAI was 32 events·h−1 at baseline, which was reduced to

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0 events·h−1 with ASV. 17 patients were followed for a period of ≥9 months and the data showed sustained ecacy with persistently low CAI. Patients remained adherent to therapy (mean adherence of 5.1±2.5 h per night).

Cao et al. (2014) randomised patients to BPAP in spontaneous/timed mode (BPAP-ST) versus new-generation ASV with a 1-night crossover design study. ASV with autotitrating EPAP was superior to BPAP-ST in normalising respiratory events including central apnoeas (parameters normalised in 83% versus 33% of patients, respectively). In contrast to the aforementioned studies, Ramar et al. (2012) reported a variable response to ASV. In this context, it must be emphasised that the algorithms of ASV devices are complex and are dierent for the dierent devices available in the USA and Europe. Successful treatment of complex SDB requires in-depth knowledge of these algorithms and the choice of appropriate pressure settings.