Treatment of Cheyne–Stokes Respiration–Central Sleep Apnea In

Home , Hypoventilation

Journal of Cardiology (2012) 59, 110—116

Available online at www.sciencedirect.com

j ournal homepage: www.elsevier.com/locate/jjcc

Review

Treatment of Cheyne—Stokes respiration—central

sleep apnea in patients with heart failure

∗

Shin-ichi Momomura (MD, PhD, FJCC)

Saitama Medical Center, Jichi Medical University, Saitama, Japan

Received 19 December 2011; accepted 22 December 2011

KEYWORDS Summary Sleep disordered breathing including obstructive sleep apnea (OSA) and central

sleep apnea (CSA) with Cheyne—Stokes respiration (CSR) is often accompanied by heart fail-

Central sleep apnea;

Cheyne—Stokes ure. Treatment of OSA centered on continuous positive airway pressure (CPAP) is established.

respiration; However, treatment of CSR-CSA is still controversial. Since CSR-CSA occurs as a consequence of

heart failure, optimization of heart failure is essential to treat CSR-CSA. For treatment directed

Oxygen therapy;

at CSR-CSA itself, a variety of treatment approaches including night oxygen therapy and non-

Continuous positive

invasive positive pressure ventilation have been applied. Among them, night oxygen therapy

airway pressure;

Adaptive improves patients’ symptoms, quality of life (QOL), and left ventricular function, but had yet

servo-ventilation been shown to improve clinical outcome. For CPAP, there are responders and non-responders

and for responders CPAP can also improve survival. Adaptive servo-ventilation (ASV), which

most effectively treats CSR-CSA, improves exercise capacity, QOL, and cardiac function. Recent

reports suggested ASV may also prevent cardiac events in patients with heart failure. However,

further studies are needed to conclude that this treatment improves patient survival.

Contents

Introduction...... 111

Mechanism of CSR-CSA in heart failure ...... 111

Treatment of CSA ...... 111

Theophylline ...... 112

Non-pharmacological treatment of heart failure ...... 112

Atrial overdrive pacing...... 113

Home oxygen therapy ...... 113

Continuous positive airway pressure...... 113

Non-invasive positive pressure ventilation...... 113

∗

Correspondence address: Division of Cardiovascular Medicine, Saitama Medical Center, Jichi Medical University, Amanuma 1-847,

Omiya-ku, Saitama-city, Saitama 330-8503, Japan.

E-mail address: [email protected]

Treatment of Cheyne—Stokes respiration—central sleep apnea in patients with heart failure 111

Adaptive servo-ventilation ...... 114

Phrenic nerve stimulation ...... 114

CO2 administration...... 115

References ...... 115

Introduction pulmonary vagal reﬂex. Hypoxemia with pulmonary conges-

tion or pulmonary edema also exacerbates hyperventilation.

As a result of hyperventilation, hypocapnea is induced.

Recent advances in management of heart failure have

Chemoreceptors detect hypocapnea and suppress neuronal

greatly improved prognosis of patients with this syndrome.

drive from the respiratory center. In normal subjects, this

However, the mortality rate of heart failure is still not low.

feedback mechanism normalizes hypocapnea and respira-

Among Japanese patients with heart failure, the annual mor-

tion is stabilized. However, in patients with heart failure, the

tality rate is 7—8% [1,2]. It is known that sleep disordered

chemoreceptor response is enhanced because of elevated

breathing is often complicated with heart failure.

sympathetic tone and excessive respiratory suppression due

There are two types of sleep apnea, obstructive sleep

to over correction by the chemoreceptor, which brings about

apnea (OSA) and central sleep apnea (CSA). OSA is a common

apnea. Once respiration ceases, blood carbon dioxide is

disease and its prevalence is high in the normal popula-

increased and hyperventilation occurs again, thus hyperven-

tion. OSA occurs due to obstruction of upper airway and

tilation and apnea/hypopnea are repeated.

closely related life style such as overweight, smoking, and

Prolonged circulation time due to low cardiac output in

alcohol drinking. OSA is associated with many cardiovascu-

heart failure also contributes to the development of CSR-

lar diseases including hypertension, coronary heart disease,

CSA. Delivery of information of blood gases such as blood CO2

arrhythmia, aortic dissection pulmonary hypertension, and

and O2 to the chemoreceptor is delayed due to prolonged

heart failure.

circulation time and this in turn delays feedback input to

On the other hand CSA is due to loss of respiratory drive

the respiratory center.

from the respiratory center and is rare among the general

Recently, Yumino et al. demonstrated that nocturnal ros-

population. While on the other hand, among a variety of

tral ﬂuid shift is also contributing to the pathogenesis of CSA

cardiovascular diseases, heart failure is the only one which

as well as OSA in patients with heart failure [8]. This ﬂuid

often accompanies CSA. CSA in the cardiovascular ﬁeld,

shift is also important as a trigger and maintaining factor of

shares a common mechanism with Cheyne-Stoke respiration,

CSR-CSA.

a weaning and waxing periodical breathing which is observed

also during waking in patients with heart failure. There-

fore, CSA and CSR are usually combined as CSR-CSA. CSR-CSA

Treatment of CSA

occurs as a consequence of heart failure. Either type of sleep

disordered breathing worsens the prognosis of patients with

heart failure [3,4]. However, the relationship to heart fail- There are reported to be many treatment approaches to

ure is different between OSA and CSA. OSA locates upstream CSR-CSA, including optimization of heart failure treatment,

of heart failure, and is important as a risk factor for car- night oxygen therapy, positive pressure ventilation, etc.

diovascular disease. On the other hand, CSR-CSA locates (Table 1, Fig. 1).

downstream of heart failure and it plays an important role Treatment of heart failure seems to be most important

in the progression of heart failure. Yumino et al. compared in the treatment of CSR-CSA. Since CSR-CSA occurs as a

background of OSA and CSR-CSA, and reported that patients result of heart failure, it is essential to optimize treatment

with CSA are older, thinner, had lower EF, and more severe of heart failure itself ﬁrst of all. Especially, beta-blockers

New York Heart Association (NYHA) class [5]. Bitter et al. improve CSR-CSA as well as heart failure itself. Tamura et al.

reported that in patients with diastolic dysfunction with reported induction of beta-blocker, carvedilol, improves

an increasing impairment of diastolic function the propor-

tion of sleep disordered breathing, and CSA in particular,

increased [6]. Thus CSA is accompanied with more severe

Table 1 Treatment of Cheyne—Stokes respiration—central

heart failure. This coincides with the fact that CSA occurs

sleep apnea with heart failure.

as a consequence of heart failure, while OSA can impair

myocardial contractility and cause development and pro- 1. Evidence based treatment of heart failure

gression of heart failure [7]. Treatment of OSA centering on 2. Continuous positive airway pressure

continuous positive airway pressure (CPAP) is established. 3. Non-invasive positive pressure ventilation (adaptive

However, treatment of CSR-CSA has not been established servo-ventilation, bi-level-positive airway pressure)

yet. 4. Night oxygen inhalation

In this article, treatment of CSR-CSA will be the focus. 5. Carbon dioxide inhalation

6. Theophylline

Mechanism of CSR-CSA in heart failure 7. Acetazolamide

8. Phrenic nerve stimulation

In patients with heart failure, pulmonary congestion occurs. 9. Atrial overdrive pacing

Pulmonary congestion leads to hyperventilation through

112 S.-i. Momomura

Heart Failure

Opmizaon of HF treatment

Screenin g of SDB by portable

moni tor

OSA susupected CSR-CS A suspected

PSG

AHI 15 AHI 15

Diagnosis and

observ aon CPAP traon treatment of

OSA

AHI 15 AHI 15

Goo d Poor

tolerance toleran ce

Connue CPAP ASV traon

AHI 15 AHI 15

Goo d Poor

Eli gible for HOT

toleran ce tolerance

Con nue ASV Intensify HF treatment HOT

Figure 1 Algorithm for the treatment of sleep disordered breathing in patients with heart failure. HF, heart failure; SDB, sleep

disordered breathing; OSA, obstructive sleep apnea; CSR-CSA, Cheyne—Stokes respiration—central sleep apnea; PSG, polysomnog-

raphy; AHI, apnea-hypopnea index; CPAP, continuous positive airway pressure; ASV, adaptive servo-ventilation; PAP, positive airway

pressure; HOT, home oxygen therapy.

CSR-CSA but not OSA in patients with heart failure due to disordered breathing, although the entire mechanism

left ventricular (LV) systolic dysfunction. through which this drug improves sleep apnea is not fully

Diuretics could also improve CSR-CSA by alleviating pul- understood.

monary congestion which is the initial event of the sequence Many years ago, Javaheri reported the short-term effect

from heart failure to CSR-CSA. Acetazolamide, is reported of theophylline on CSR-CSA [10]. This effect of theophylline

to improve CSR-CSA in patients with CSR-CSA. The mecha- was attested by Hu et al. in an Asian population with heart

nism of the effect of acetazolamide is ﬁrstly its respiratory failure [11]. Theophylline also has a positive inotropic effect

stimulating effect and secondly its diuretic effect. However through phosphodiesterase III inhibitory action. However,

acetazolamide is not a ﬁrst-line diuretic for the treatment of every drug which has positive inotropic effects including

heart failure. Furosemide is the most widely used diuretic phosphodiesterase inhibitors has a negative impact on mor-

for the treatment of heart failure. However, so far there tality in patients with chronic heart failure due to depressed

is no report which demonstrated that furosemide improves LV dysfunction. Thus theophylline is not recommended for

CSR-CSA, although it improved OSA [9]. In patients with patients with heart failure especially due to LV systolic dys-

heart failure, body ﬂuid shifts to upper body while patient function.

is sleeping at night. This ﬂuid shift may contribute to the

development of CSA by enhancing pulmonary congestion, a

trigger of the sequence of CSR-CSA as well as OSA by increas- Non-pharmacological treatment of heart

ing airway edema (nocturnal rostral ﬂuid shift is a unifying failure

concept for the pathogenesis of OSA and CSA in men with

heart failure) [8]. Therefore normalization of ﬂuid status

Non-pharmacological treatment of heart failure also

with diuretics in patients with heart failure is essential.

improves CSR-CSA. In 2004, Sinha et al. reported that

resynchronization brought a signiﬁcant decrease in apnea-

Theophylline hypopnea index (AHI) and sleep quality index (10.4 1.6 to

3.9 ± 2.4, p < 0.001) without CSR and a signiﬁcant increase in

Theophylline stimulates respiration by competing with SaO2 min (84 ± 5% to 89 ± 2%, p < 0.001) in 14 patients with

adenosine, a respiratory depressant and improves sleep CSR-CSA, while there was no signiﬁcant change in AHI, and

Treatment of Cheyne—Stokes respiration—central sleep apnea in patients with heart failure 113

SaO2 min in patients without CSA [12]. This ﬁnding is sup- Continuous positive airway pressure

ported by a recent meta-analysis [13]. In this meta-analysis,

170 patients from six manuscripts and three abstracts were

CPAP was originally a standard treatment for OSA by sup-

included. After treatment with cardiac resynchronization

plying pressure higher than the obstructive pressure of the

therapy, a signiﬁcant reduction in AHI was found in patients

airway and not speciﬁcally designed to treat CSR-CSA. How-

with CSA with a mean reduction of −13.05 (CI −16.74 to

ever, CPAP may also reduce CSR-CSA in patients with heart

−

9.36; p < 0.00001) but not in patients with OSA.

failure through its unloading effect. CPAP reduces LV preload

by supplying positive pressure to thoracic cage and improves

pulmonary congestion. This may attenuate hyperventilation

Atrial overdrive pacing through pulmonary vagal irritant receptors and subsequent

CSR. In fact in 2000, Sin et al. reported the results of a

In 2002, Garrigue reported that atrial pacing improves randomized study. In this study CPAP improved survival in

CSR-CSA as well as OSA [14] in patients with pacemaker patients with heart failure and CSR-CSA [24]. This has led

implantation because of the treatment of bradycardia. to the CANPAP, a large-scale randomized study to evaluate

Meta-analysis also showed that overdrive atrial pacing the effect of CPAP on survival in patients with heart failure

reduces AHI in patients with predominantly CSA [15]. How- complicated with CSR-CSA [25]. As is well known, although

ever the additional effect of atrial overdrive pacing on CPAP did not improve survival it attenuated CSA, improved

CSR-CSA in patients with heart failure was only small [16]. nocturnal oxygenation, increased the ejection fraction, low-

Thus atrial overdrive pacing should not be applied simply to ered norepinephrine levels, and increased exercise capacity

treat CSR-CSA. evaluated by 6 min walk distance. Sub-analysis of CANPAP by

Arzt et al. had some positive impact [26]. In 57 patients out

of 110 in the CPAP group, AHI was improved to below 15.

In this group, CPAP treatment resulted in a greater increase

Home oxygen therapy

in LV ejection fraction at 3 months and signiﬁcantly bet-

ter transplant-free survival than control subjects, whereas

Originally in 1989, Hanly et al. reported that the acute effect

in the rest of the patients, whose AHI remained above 15,

of nocturnal oxygen therapy on CSR corrects hypoxemia, and

neither LV ejection fraction or survival was improved. Thus

consolidates sleep by reducing arousals caused by the hyper-

there are ‘‘responders’’ and ‘‘non-responders’’ to CPAP

pneic phase of CSR [17]. A decade after the ﬁrst report by

in heart failure patients with CSR-CSA. ‘‘Non-responders’’

Hanly, Javaheri also reported that oxygen inhalation acutely

are older, had more severe sleep disordered breathing,

improved CSR in patients with heart failure and this effect

and a larger fraction of central component compared with

of oxygen, however, may be modulated by the level of arte-

‘‘responders’’. Five years before the results of CANPAP were

rial PCO2 [18]. However in these studies the effects of

published, Javaheri reported that there are responsive and

oxygen inhalation to indexes of heart failure, including ejec-

non-responsive patients whose CSA was acutely treated by

tion fraction and NYHA class were not evaluated. In 1996,

CPAP [27]. Moreover non-responsive patients had higher AHI

Andreas et al. demonstrated that successful treatment of

and more pure CSA. Thus, CPAP has a limited effect on the

CSR with nocturnal nasal oxygen improves not only sleep, but

treatment of patients with heart failure and CSR-CSA.

also exercise tolerance and cognitive function in patients

with congestive heart failure [19]. More recently, three ran-

domized studies were presented from Japan [20,21]. In the Non-invasive positive pressure ventilation

short-term study by Sasayama et al., night oxygen inhala-

tion improved CSR-CSA as well as LV function and quality of

Bi-level positive airway pressure (PAP) was originally used to

life assessed by speciﬁc activity scale. In the 1-year study,

treat patients’ respiratory failure and supply oblong pres-

home oxygen therapy (HOT) was well tolerated and the

sure support to forcibly ventilate these patients. On the

beneﬁt on LV function and quality of life observed in the 12-

assumption that bi-level PAP may also treat CSR-CSA, clin-

week trial was maintained over a prolonged period although

ical studies were performed in heart failure patients with

this study failed to show beneﬁt on the primary compos-

CSR-CSA. Dohi et al. treated 20 heart failure patients with

ite cardiac endpoints of combined rate of cardiac death,

CSR-CSA ﬁrst with CPAP for one night and then with bi-level

hospitalization because of worsening heart failure, and a

PAP in 11 patients in whom AHI remained >15 with CPAP.

decrease in the Speciﬁc Activity Scale by ≥1 Mets, because

Those who were unresponsive to CPAP had signiﬁcantly lower

of the small sample size. Another randomized study reported

PCO2, higher plasma brain natriuretic peptide (BNP), longer

by Japanese researchers demonstrated that HOT improves

mean duration of CSR and fewer obstructive episodes than

exercise capacity, cardiac function, and cardiac sympathetic

CPAP responders. Among these 11 patients, 7 were chroni-

nerve activity in patients with congestive heart failure and

cally treated with bi-level PAP for 6 months with improved

CSA [22]. Thus, in Japan, HOT is approved for reimburse-

LV ejection fraction [28]. Thus they concluded bi-level PAP

ment by public health insurance in patients with NYHA class

could be an effective alternative for patients with heart fail-

III or IV, with optimal medical therapy for heart failure and

ure and pure CSR-CSA who are unresponsive to CPAP. Kasai

AHI higher than 20 by polysomnography.

treated 7 heart failure patients complicated with CSR-CSA

The mechanism of night oxygen therapy is not fully

with bi-level PAP and compared with the same number of

understood, but by maintaining PO2 level with night oxygen

patients with conventional therapy. Bi-level PAP signiﬁcantly

therapy sympathetic hyperactivity is alleviated [23] and may

improved LV ejection fraction, mitral regurgitation, BNP, and

normalize VE/PCO2 relationship in CSR.

NYHA class [29]. Similarly, Noda et al. treated 52 dilated

114 S.-i. Momomura

cardiomyopathy patients with coexisting CSR-CSA with bi- with CPAP in patients with chronic heart failure and coex-

level PAP and found that bi-level PAP improves LV function isting CSR-CSA and OSA [43]. In this study, 31 patients

as well as CSR-CSA [30]. Thus bi-level PAP is more effective with chronic heart failure, deﬁned as LV ejection frac-

than CPAP in treating CSR-CSA and improves LV function. tion <50% and NYHA class ≥II, with coexisting obstructive

However the problem of bi-level PAP was its low compliance, sleep apnea and CSR-CSA, were randomly assigned to either

and it could not be taken over CPAP. CPAP or ﬂow-triggered ASV. The suppression of respiratory

events, changes in cardiac function, and compliance with

the devices during the 3-month study period, improvements

Adaptive servo-ventilation in quality-of-life and LV ejection fraction were greater in

the ASV group. Compliance was signiﬁcantly greater with

To date, the most effective treatment for CSR-CSA is adap- ASV than with CPAP and there was a signiﬁcant correlation

tive servo-ventilation (ASV). Teschler et al. compared the between machine using time and improvement in LV ejec-

effect of one night of ASV on sleep and breathing with the tion fraction when data from both groups were plotted on

effect of other treatment modalities including nasal oxy- the same plane.

gen (2 L/min), CPAP (mean 9.25 cm H2O), bi-level PAP (mean Thus ASV (adaptive servo-ventilation or auto servo-

13.5/5.2 cm H2O), or ASV largely at the default settings ventilation) improves cardiac function, exercise capacity,

(mean pressure 7—9 cm H2O) during polysomnography in 14 and quality of life, but its effect on survival in patients

subjects with stable cardiac failure and receiving optimal with heart failure is unknown. Recently, Yoshihisa reported

medical treatment. These four treatment modalities were that clinical events including cardiac death or hospitaliza-

tested on four treatment nights in random order. They found tion are signiﬁcantly lower in heart failure treated with

that one night ASV more strongly suppresses CSA and/or CSR ASV compared with those not treated with ASV. Koyama

(CSA/CSR) in heart failure and improves sleep quality bet- et al. reported that the effects of ASV on clinical events

ter than any other treatment modalities [31]. Since then, and LV function were demonstrated regardless of the sever-

an increasing number of reports on ASV effects in patients ity of sleep apnea [44]. Takama reported ASV treatment

with heart failure and sleep disordered breathing have been for patients with mild sleep disordered breathing resulted

published [32—38]. in almost equal improvements in BNP levels and LV ejec-

Pepperell demonstrated signiﬁcant falls in plasma BNP tion fraction compared to that in patients with moderate

and urinary metadrenaline excretion with 1 month active and severe sleep disordered breathing [45]. The results of

treatment compared with subtherapeutic patients [32]. Old- these reports may indicate that ASV improves heart fail-

enburg demonstrated that ASV improved indexes of exercise ure regardless of sleep disordered breathing. However, in

capacity including anaerobic threshold (AT), peak oxygen Koyama’s study, AHI in two groups with patients with non-to-

uptake, and peak workload as well as improvement in LV mild sleep disordered breathing were 14.2 and 15.6, which

ejection fraction and blood N terminal pro-BNP level in were actually not very mild. And in Takama’s report, the

patients with heart failure due to LV systolic dysfunction improvement in LV ejection fraction was relatively mild and

[39]. not signiﬁcant in the mild sleep disordered breathing group

The effect of ASV is not limited to heart failure patients (AHI, 20) although there was no difference in the LV ejection

with reduced LV ejection fraction but extended to those with fraction after ASV therapy between the groups. But these

preserved LV ejection fraction. Bitter et al. reported ASV reports raise the question if the mechanism of improvement

effectively attenuates CSR in 39 patients with heart failure in heart failure by ASV may not be through its effect on

and normal LV ejection fraction and improves heart fail- sleep disordered breathing. Even without sleep disordered

ure symptoms and cardiac function, especially echo-Doppler breathing, ASV decreases LV preload and afterload by sup-

indexes of diastolic function [40]. Superiority of ASV to other plying positive intrathoracic pressure. Expansion of the lung

treatments has also been reported. Phillipe et al. random- by breath-by-breath pressure support of ASV may amelio-

ized patients to ASV and CPAP [33]. They found that both rate the increased sympathetic tone in patients with heart

ASV and CPAP decreased the AHI but, noticeably, only ASV failure.

−1

completely corrected CSA—CSR, with AHI below 10 h . At According to Haruki et al. the acute beneﬁcial impact

3 months, compliance was comparable between ASV and of ASV is mainly associated with the reduction of afterload

CPAP; however, at 6 months compliance with CPAP was sig- resulting in an increase in stroke volume and cardiac out-

niﬁcantly less than with ASV. At 6 months, the improvement put. In contrast, chronic ASV therapy produces LV and left

in quality of life was higher with ASV and only ASV induced a atrial reverse remodeling resulting in an improvement in LV

signiﬁcant increase in LV ejection fraction. Campbell et al. function and the severity of mitral regurgitation in patients

compared two treatments for CSA—CSR, night oxygen ther- with chronic heart failure [46]. These effects of ASV may

apy and ASV in patients with chronic heart failure using a well be exerted without direct effect on sleep disordered

cross over design [41]. They found that CSA—CSR is reduced breathing.

to a greater extent by ASV than oxygen therapy over 8 weeks Tw o randomized trials evaluating the effect of ASV on

but was not accepted long term. However, neither treatment survival are ongoing currently.

improved prognostic indices of heart failure or symptoms in

the short term. Eight weeks was probably too short to show

improvement in LV function for both treatment modalities. Phrenic nerve stimulation

Another type of ASV (auto servo-ventilation) also effec-

tively treats CSR-CSA [42]. Kasai et al. reported the results Recently Ponikowski et al. reported that unilateral

of randomized study, J-ASV, of this device in comparison transvenous phrenic nerve stimulation signiﬁcantly reduces

Treatment of Cheyne—Stokes respiration—central sleep apnea in patients with heart failure 115

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