Bi-level positive pressure ventilation and adaptive servo ventilation in patients with heart failure and Cheyne-Stokes respiration

Sleep Medicine 9 (2008) 652–659 www.elsevier.com/locate/sleep

Original Article

Bi-level positive pressure ventilation and adaptive servo ventilation in patients with heart failure and Cheyne-Stokes respiration Ingo Fietze a

a,*

, Alexander Blau a, Martin Glos a, Heinz Theres b, Gert Baumann b, Thomas Penzel a

Charite – Universita¨tsmedizin Berlin, CCM, Department of Internal Medicine, Center for Sleep Medicine, Luisenstr. 13, D-10117 Berlin, Germany b Charite – Universita¨tsmedizin Berlin, CCM, Department of Internal Medicine, Clinic for Cardiology and Angiology, Luisenstr. 13, D-10117 Berlin, Germany Received 23 March 2007; received in revised form 14 September 2007; accepted 18 September 2007 Available online 19 November 2007

Abstract Objectives: Nocturnal positive pressure ventilation (PPV) has been shown to be effective in patients with impaired left ventricular ejection fraction (LVEF) and Cheyne-Stokes respiration (CSR). We investigated the effect of a bi-level PPV and adaptive servo ventilation on LVEF, CSR, and quantitative sleep quality. Methods: Thirty-seven patients (New York heart association [NYHA] II–III) with LVEF < 45% and CSR were investigated by electrocardiography (ECG), echocardiography and polysomnography. The CSR index (CSRI) was 32.3 ± 16.2/h. Patients were randomly treated with bi-level PPV using the standard spontaneous/timed (S/T) mode or with adaptive servo ventilation mode (AutoSetCS). After 6 weeks, 30 patients underwent control investigations with ECG, echocardiography, and polysomnography. Results: The CSRI decreased significantly to 13.6 ± 13.4/h. LVEF increased significantly after 6 weeks of ventilation (from 25.1 ± 8.5 to 28.8 ± 9.8%, p < 0.01). The number of respiratory-related arousals decreased significantly. Other quantitative sleep parameters did not change. The Epworth sleepiness score improved slightly. Daytime blood pressure and heart rate did not change. There were some differences between bi-level PPV and adaptive servo ventilation: the CSRI decreased more in the AutoSetCS group while the LVEF increased more in the bi-level PPV group. Conclusions: Administration of PPV can successfully attenuate CSA. Reduced CSA may be associated with improved LVEF; however, this may depend on the mode of PPV. Changed LVEF is evident even in the absence of significant changes in blood pressure. Ó 2007 Elsevier B.V. All rights reserved. Keywords: Heart failure; Cheyne-Stokes respiration; Positive pressure ventilation; Sleep apnea; Central sleep apnea; Adaptive servo ventilation; Bilevel positive airway pressure; Left ventricular ejection fraction

1. Introduction Sleep-related breathing disorders are effectively treated with positive pressure ventilation (PPV) therapy. Not only patients with obstructive sleep apnea (OSA) benefit from this therapy but also patients with central sleep-related breathing disorders. Central sleep-related *

Corresponding author. Tel.: +49 30 4505 13160; fax: +49 30 4505 13906. E-mail address: ingo.fi[email protected] (I. Fietze). 1389-9457/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2007.09.008

breathing disorders and Cheyne-Stokes respiration (CSR) in particular are common in patients with heart failure. Approximately 40% of patients with an impaired left ventricular ejection fraction (LVEF) suffer from central sleep-related breathing disorders, which increases their mortality [1–4]. To reduce mortality and improve quality of life, sleep-related breathing disorders should be treated in patients with heart failure. Oxygen therapy can reduce CSR to a limited extent only [5]. The application of respiratory stimulants, carbon dioxide and atrial

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overdrive pacing are further means of treatment. Continuous positive airway pressure (CPAP) has proven to reduce CSR [6–8] and to improve LVEF when controlled after 1–3 months [3,9]. This beneficial effect has been shown in patients with chronic heart failure (CHF) and OSA as well [10,11]. In contrast, the Canadian positive airway pressure (CANPAP) trial showed that conventional CPAP decreased AHI only by 50% and CPAP was only tolerated for 3.5 h/night [12]. When considering the CPAP responder with an AHI below 15/h, this treatment was effective in abolishing CSR and improving LVEF and transplant-free survival [8]. The CANPAP study did not demonstrate improvements in sleep quality nor in the number of nocturnal arousals. Due to this negative result and due to the persistent clinical need to effectively reduce central apneas and to improve patient comfort, the search for alternative treatment modes besides CPAP [13] motivated this study. Bi-level PPV is an alternative ventilation mode for patients with impaired LVEF and CSR [14]. Similar to data with CPAP, a few studies using bi-level PPV indicated that this ventilation mode can effectively reduce CSR, improve sleep quality, and increase LVEF in CHF patients [15–18]. With the new ventilation technique, adaptive servo ventilation (ASV), similar positive effects on CSR and sleep quality were reported [16,19,20]. Pepperell et al. [20] did not report an effect on LVEF after 1 month of ASV support in CHF patients with central sleep apnea, although a significant decrease in brain natriuretic peptide (BNP) was observed. In contrast, Philippe et al. [19] reported for the first time an increase of LVEF over a period of 6 months in their ASV group compared to CPAP treated CHF patients. Still results are contradicting regarding cardiovascular outcome and sleep characteristics with ASV therapy. More specifically, there are very few studies using bilevel PPV in CHF patients. For a selected patient population with heart failure and severe LVEF impairment, without complaints about sleep-disordered breathing (SDB) we wanted to test the efficacy of two ventilation modes: bi-level PPV spontaneous/timed (S/T) and ASV on CSR, sleep quality, and LVEF. 2. Methods 2.1. Subjects A total of 129 patients with stable, pharmacologically treated CHF (LVEF < 45%, New York heart association [NYHA] functional class II–III) were screened in order to detect CSR, using an ambulatory polygraph with oximetry, heart rate, oronasal airflow, snoring sounds, and abdominal respiratory effort (Embletta; Embla Systems, Denver, Co, USA). Visual evaluation revealed that 42 patients had CSR with a respiratory

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disturbance index (RDI) > 15/h, with less than 20% obstructive respiratory events. Inclusion and exclusion criteria were similar to the study of Ko¨hnlein et al. [17]. Based on the recording of the ambulatory polygraph, nocturnal time during which there were snoring sounds was evaluated. Patients had to have less than 10% of the night’s recording with accompanying snoring sounds. These patients were asked to participate in this prospective PPV study. Thirty-seven patients agreed (34 males, 3 females; mean age 58.9 ± 10.4 years, mean body mass index (BMI) 28 ± 3.9 kg/m2). Patients completed a cardiology examination with echocardiography, blood pressure, heart rate measurements, and pulmonary function test, blood–gas analysis. Exclusion criteria were decompensated heart failure, change in medication 2 weeks prior to the study, myocardial infarction within the last 3 months, occurrence of stroke within the previous 12 months, tachycardic atrial fibrillation, unstable angina, obstructive pulmonary disease requiring systemic therapy, and any other acute medical disease. Patients had to be naı¨ve to PPV and should not have received oxygen therapy. The study protocol was approved by the Ethics Committee of the Charite´ university hospital and written informed consent was obtained from all patients. 2.2. Study protocol Patients received a cardiorespiratory polysomnography at a baseline night in order to confirm the diagnosis and in order to have the same recording setting for the diagnostic and treatment nights. Polysomnography was performed according to standard criteria using the Embla A10 recorder together with the Somnologica software; Embla Systems, Denver, Co, USA. During the following night, patients were randomly assigned to one of the two ventilation modes. Either they received a bi-level S/T mode device (VPAPII-ST; ResMed, Sydney, Australia) or they received an ASV mode device (AutoSetCS; ResMed, Sydney, Australia). During the third night, a fine-tuning of the titrated ventilation pressure setting was performed. Thereafter patients continued with the ventilation mode as assigned. Table 1 lists patient characteristics of both treatment groups. After 6 weeks, patients returned to the sleep center and underwent another cardiorespiratory polysomnography. Thirty patients participated in the control study. The seven patients who did not return did not differ in terms of CSA, BMI, LVEF, or age. The cardiology examination with echocardiography, blood pressure, and heart rate measurements was also repeated. Calculation of the LVEF was performed using twodimensional and M-mode echocardiography. All cardiorespiratory examinations were conducted 2–3 h after

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Table 1 Baseline characteristics of the AutoSetCS and the group given VPAPII-ST Characteristica

AutoSetCS (N = 17)

VPAPII-ST (N = 20)

Age [years] Sex BMI [kg/m2]b ESSc

61.9 ± 9.1 (m = 15, f = 2) 26.9 ± 2.4 10.1 ± 4.2

56.4 ± 10.9 (m = 19, f = 1) 28.9 ± 4.8 10.2 ± 4.3

Daytime blood pressure [mmHg] Systolic Diastolic

108.0 ± 17.1 67.3 ± 9.0

103.5 ± 15.1 66.0 ± 9.0

Cause of heart failure [N] DCMP ICMP

12 5

12 8

NYHA class [N] II III

10 7

9 11

5 (29) 3 (18) 3 (18)

9 (45) 3 (15) 5 (25)

13 (76)

17 (85)

Cardioverter/defibrillator [N(%)] Pacemaker [N(%)] Myocardial infarction and ICMP [N(%)] Beta-blocker medication [N(%)]

Values are means ± standard deviation or number. AutoSetCS, patient group given the AutoSetCS device; VPAPII-ST, patient group given the VPAPII-ST device. BMI, body mass index; ESS, Epworth sleepiness scale; DCMP, nonischemic dilated cardiomyopathy; ICMP, ischemic dilated cardiomyopathy; NYHA, New York heart association. a There were no significant differences between the two groups in any of the variables. b The BMI is the weight in kilograms divided by the square of the height in meters. c The Epworth sleepiness scale ranges from 0 to 24, with scores of 10 or higher indicating excessive daytime sleepiness.

patients got up in the morning (between 9 and 11 a.m.). The investigators of the echocardiography were blinded to the mode of ventilation treatment. Blood pressure was measured while patients were in a seated position during the daytime according to the protocol established in the Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) project [21]. 2.3. Titration protocol for ventilation therapy The titration of pressure for ventilation was done by the attending personnel during the second and third night of cardiorespiratory polysomnography. For the ASV patients, we chose an expiratory positive airway pressure (EPAP) of 4 cmH2O, which was the agreed preset value also for two parallel studies [16,17]. We applied a pressure swing between 4 and 10 cmH2O, which corresponds to the difference between end-inspiratory and end-expiratory pressure. To preset the respiratory frequency was not needed because the ASV device calculates this on the basis of the patient’s spontaneous frequency [16]. The mean nocturnal pressure calculated

as mean pressure between EPAP and inspiratory positive airway pressure (IPAP) remained between 7 and 9 cmH2O in all ASV patients. In 13 patients, EPAP was increased to 5 and 6 cmH2O in order to eliminate remaining obstructive apnea events and thereby optimize treatment. Pressure settings were set manually for the bi-level S/T patients. For all patients, the initial values were 4 cmH2O expiratory and 8 cmH2O inspiratory pressure. We applied respiratory rates between 13 and 18 breaths per minute. The duty cycle was set to values between 33% and 40%. Expiratory pressure was increased only when obstructive events occurred during the recording. Mean expiratory pressure was 5.4 ± 0.8 cmH2O (range 4–7). The inspiratory pressure was increased at the occurrence of CSR, and on the basis of the patient’s compliance by steps 1 cmH2O until the disappearance of CSR. The final mean value was 11.8 ± 1.8 cmH2O (range 8–14). All patients were equipped with a full face mask. Twenty-four patients suffered from acute rhinitis and received a warm-air humidification in addition. 2.4. Evaluation of data The evaluation of polysomnography was done using standard criteria for sleep stages (Rechtschaffen and Kales [22]) and respiratory events (American Academy of Sleep Medicine [AASM]). For respiration we carefully looked for events with Cheyne-Stokes respiration (CSR-CSA) and for periodic breathing (PB). Unlike CSR-CSA, the pattern of periodic breathing does not contain central apneas. Respiratory and movement arousals were evaluated as well [23]. We calculated the following values: the CSR-CSA index (CSAI), the PB index (PBI), the Cheyne-Stokes respiration index (CSRI, the sum of CSAI and PBI), the obstructive apnea index (OAI), the mixed apnea index (MAI) and the RDI (the sum of CSRI, OAI and MAI). The duration of each Cheyne-Stokes cycle was evaluated as the time from the beginning of ventilation to the end of the following central apnea. We further analyzed the oxygen desaturation index (ODI) and the duration of central apneas, and calculated the duration of a periodic respiratory cycle from peak to peak. 2.5. Statistical analysis Results were given as means ± standard deviation (SD) values. Wilcoxon’s rank test was used to evaluate differences within patient groups. Kruskal–Wallis test and Mann–Whitney U-test for post hoc analyses were used to evaluate differences between patient groups. Statistical analyses were performed using the software package SPSS for Windows (version 11.0, SPSS Inc., Chicago, IL, USA). Differences were considered significant when a two-tailed p value < 0.05 was found.

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Table 3 Sleep data from polysomnography

3. Results The study showed a significant reduction in CSR for all patients receiving either mode of therapy. Nevertheless, in five patients we detected persistent SDB (> 15/h) under therapy (3 VPAP, 2 ASV). Three patients demonstrated an appreciable decrease in CSAI, but ultimately were unable to achieve an efficient adaptation setting to the variable positive airway pressure (VPAP) therapy. One patient had a higher RDI after VPAP therapy than before. Results for breathing, oxygen saturation, and nocturnal heart rate before therapy and 6 weeks with treatment are shown in Table 2. There were no differences between the groups receiving AutoSetCS and VPAPII-ST regarding CSRI, OAI, MAI, duration of pathological breathing events, and nocturnal oxygen saturation at baseline and after 6 weeks of treatment. We detected no adverse effects of treatment. Patients who completed the study had a ventilation therapy compliance rate with an average nightly use of 4.8 h. For the full group of 30 patients, the LVEF improvement was significant (from 25.1 ± 8.5% to 28.8 ± 9.8%, p < 0.01). For those CHF patients who received the VPAPII-ST device for treatment, a significant increase of LVEF evaluated by echocardiography was found after 6 weeks (p < 0.01). The small increase in the AutoSetCS group was not significant (Table 2). Other echocardiographic parameters such as end-diastolic diameter and shortening fraction did not change under any ventilation therapy; pulmonary function and respiratory drive did not change either. There was

AutoSetCS Baseline

VPAPII-ST 6 weeks

Baseline

6 weeks

TST [min] 354.7 ± 82.6 343.5 ± 65.7 325.3 ± 52.0 311.7 ± 80.6 ASL [min] 19.8 ± 14.6 19.9 ± 13.6 20.7 ± 16.5 23.7 ± 17.3 S1 [%] 40.1 ± 14.1 31.8 ± 14.5 34.7 ± 14.6 36.6 ± 14.9 S2 [%] 35.1 ± 10.7 38.1 ± 12.0 39.3 ± 10.8 36.0 ± 17.1 S1 + S2 [%] 75.1 ± 10.4 70.0 ± 11.7 73.9 ± 11.3 72.6 ± 10.5 S3 [%] 9.3 ± 6.1 13.0 ± 7.0 12.2 ± 8.2 11.2 ± 6.2 S4 [%] 2.1 ± 4.0 3.4 ± 4.4 1.7 ± 2.3 2.7 ± 4.3 S3 + S4 [%] 11.4 ± 8.0 16.5 ± 9.2 13.6 ± 8.9 13.9 ± 8.3 NREM [%] 86.5 ± 7.3 86.5 ± 6.4 87.5 ± 7.9 86.5 ± 8.2 REM [%] 13.5 ± 7.4 13.4 ± 6.4 11.4 ± 6.1 13.5 ± 8.2 RERA [1/h] 18.4 ± 11.6 8.4 ± 11.9* 23.4 ± 11.6 10.9 ± 12.7* MVA [1/h] 2.6 ± 2.1 4.7 ± 4.6 4.7 ± 4.7 10.2 ± 12.5 Values are means ± standard deviation. AutoSetCS, patient group given the AutoSetCS device; VPAPII-ST, patient group given the VPAPII-ST device; TST, total sleep time; ASL, asleep latency; S1, sleep stage 1; S2, sleep stage 2; S1 + S2, sum of sleep stages 1 and 2; S3, sleep stage 3; S3 + S4, sum of sleep stages 3 and 4; NREM, non-rapid eye movement sleep; REM, rapid eye movement sleep; RERA, respiratory-related arousals; MVA, movement arousals. Six weeks vs. baseline within groups: *p < 0.01. Neither in baseline values nor in 6-week values were differences found between the AutoSetCS group and the group given VPAPII-ST.

no change in systolic blood pressure, diastolic blood pressure, or heart rate after ventilation therapy, and no differences were detected with respect to the treatment mode. Quantitative sleep evaluation revealed a significant decrease of respiratory-related arousals. No other sleep parameters showed clear changes after 6 weeks of treatment (Table 3).

Table 2 LVEF and cardiorespiratory data from polysomnography AutoSetCS

LVEF [%] ESS Mean O2 [%] Mean HR [1/min] PBI [1/h] CSAI [1/h] CSRI [1/h] OAI [1/h] MAI [1/h] RDI [1/h] ODI [1/h] PB-duration [s] CA-duration [s]

VPAPII-ST

Baseline

6 weeks

Baseline

6 weeks

24.6 ± 7.9 10.1 ± 4.4 92.6 ± 4.0 62.8 ± 8.6 16.2 ± 8.3 14.8 ± 14.3 31.0 ± 10.0 0.4 ± 0.7 0.2 ± 0.7 31.7 ± 9.8 26.5 ± 12.2 33.6 ± 8.5 14.8 ± 14.3

26.5 ± 8.8 8.7 ± 3.9 94.4 ± 2.4 63.9 ± 9.8 8.5 ± 6.2  2.5 ± 4.4à 11.1 ± 9.9à 0.2 ± 0.4 0.0 ± 0.0 11.2 ± 9.4à 14.7 ± 11.0* 31.8 ± 7.8 10.3 ± 10.2

25.5 ± 9.2 10.2 ± 4.3 93.4 ± 2.5 66.1 ± 11.1 17.6 ± 11.3 15.8 ± 18.2 33.4 ± 20.5 0.3 ± 1.2 0.0 ± 0.1 34.9 ± 20.4 33.3 ± 34.0 33.5 ± 10.0 15.8 ± 18.2

31.1 ± 10.5  8.1 ± 3.5 93.5 ± 3.0 64.9 ± 15.6 14.4 ± 15.8 1.6 ± 4.8  16.1 ± 16.2  0.3 ± 0.5 0.0 ± 0.2 16.4 ± 16.1  12.4 ± 15.0* 32.7 ± 8.9 9.8 ± 9.3

Values are means ± standard deviation. AutoSetCS, patient group given the AutoSetCS device; VPAPII-ST, patient group given the VPAPII-ST device; LVEF, left ventricular ejection fraction; ESS, Epworth sleepiness scale; HR, heart rate; PBI, periodic breathing index; CSAI, Cheyne-Stokes apnea index; CSRI, Cheyne-Stokes respiration index; OAI, obstructive apnea index; MAI, mixed apnea index; RDI, respiratory disturbance index; ODI, oxygen desaturation index; PB, periodic breathing; CA, central apnea. Six weeks vs. baseline within groups: *p < 0.05,  p < 0.01, àp < 0.001. Neither in baseline values nor in 6-week values were differences found between the AutoSetCS group and the group given VPAPII-ST. Six weeks vs. baseline within groups: *p < 0.05,  p < 0.01, àp < 0.001. Neither in baseline values nor in 6-week values differences were found between the AutoSetCS group and the group given VPAPII-ST.

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Self-reported daytime sleepiness assessed by the Epworth sleepiness scale (ESS) showed no improvement in either group, and no relevant differences between the groups (Table 2). Out of seven patients who entered but did not complete this study, one patient received a heart transplant during the study period (VPAP patient). Five patients did not tolerate the treatment due to problems with the mask (3 VPAP, 2 ASV) and one patient (VPAP) received a late-onset infection of his pacemaker pocket. The other 30 patients continued the therapy after completion of the study. Periodic breathing remained in nine of these patients. We changed one patient from AutoSetCS to VPAPII-ST and another patient from the VPAPII-ST to the AutoSetCS mode. We optimized the ventilation pressure for the remaining seven patients. 4. Discussion In a patient population, primarily with no complaint about SDB and with stable chronic heart failure with severe LVEF impairment, we first selected patients who had CSR. For this selection we used an ambulatory polygraph, which was acceptable to these patients, and then confirmed the diagnosis by cardiorespiratory polysomnography. In a 6-week treatment trial we found an increase in LVEF on the basis of effective PPV treatment of CSR using two titration nights in the sleep laboratory. These results confirm the findings of earlier studies where an increase in LVEF after 1–3 months of therapy with CPAP or after 3–6 months with bi-level S/T or ASV treatment in CHF patients with CSR was reported [3,15,19,18,24,25]. Philippe et al. [19] found an improvement of ASV treatment for LVEF in 13 CHF patients with CSR. In a small group (n = 10) with bi-level PPV, Noda et al. [18] found a marked increase. The initial LVEF of patients in both studies was not as low as in our population. In our study, we found an increase in LVEF from 25% to 29% based on a similar patient population as studied previously with CPAP [25]. We assume there are specific reasons for the marked LVEF increase from 31% to 51% reported by Noda et al. [18]. They investigated patients with a higher initial LVEF (>25%) and better NYHA classes. The subjects were younger with well-treated CSR (AHI < 10/h) for more than 3 months. The ventilation therapy settings were different; the mean EPAP was clearly higher than in our subjects. It has to be considered that the existing CHF trials have studied patient groups which are not comparable, specifically in terms of severity, and background of heart failure (pathophysiological reasons, duration of impairment, concomitant medical therapy). This is independent from the actual trial regarding the application of ventilation therapy. One common feature of ventilation modes reported in all studies until now is the application of low pres-

sures. We applied an ASV pressure similar to other studies [16,20]. The mean EPAP for bi-level therapy (5.4 ± 0.8 cmH2O) is comparable to other studies [15– 17] but lower than that used by the Noda group (7.9 ± 0.9 cmH2O) [18]. We conclude that the relatively low pressure applied by many studies in CHF in contrast to higher pressure applied for OSAS therapy is evidently sufficiently effective. One clear limitation of our protocol is the lack of a LVEF-matched placebo treatment group. Another limitation is the relatively small sample size. Therefore, the difference in results observed between bi-level PPV and ASV treatment may not hold true for larger studies. We did not expect this difference and it is difficult to explain. The difference may indicate that an individual choice of pressure ventilation mode (bi-level PPV, ASV) and adaptation of ventilation therapy is needed, which considers more details of the underlying heart failure problem. However, we see that both ventilation modes were able to eliminate central breathing disorders during sleep much more effectively than using CPAP, which is certainly due to the different IPAP and EPAP pressure selection. The remaining difference between bi-level PPV and ASV is that the mean applied pressure varies in ASV during the night, whereas it is fixed in bi-level PPV. Changing pressure levels during the night may be have a different effect on blood pressure and other circulatory parameters, which may influence the sympathetic outflow in different ways. To date, little is known about the nocturnal effect of pressure ventilation in CHF in addition to the effect of eliminating CSR. Finally, the study was not conducted to detect differences between the two ventilation modes but to prove that the new ASV therapy is comparable to the established bi-level S/T PPV. Our results show that this is indeed the case. With this result we have to consider that the titration of the bi-level ventilation is more difficult for the personnel and that subjective compliance according to subjective sleep quality assessment seems to be better using ASV. Furthermore, while significant changes may be present in a subgroup of patients with regard to LVEF there is no evidence from our study that the PPV intervention changed long-term hard endpoints. Surprisingly the CANPAP trial [12] was also unable to provide evidence from a sufficiently representative patient population about whether ventilation therapy could indeed serve as a valid non-pharmacological intervention for CHF patients with CSR, that is, one that enhances quality of sleep, reduces cardiovascular risk, lowers mortality and improves subjective sensations of health. A post hoc analysis of data with effective ventilation therapy showed an improved LVEF and a longer transplant-free survival interval for subjects with an AHI < 15/h in contrast to subjects with an AHI > 15/h [8].

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The effect of PPV on the LVEF of CHF patients may be based on different pathophysiological mechanisms. PPV therapy, regardless of the ventilation mode, enhances functional residual capacity and, in turn, pulmonary oxygen store; reduces sympathetic activity [9] which is enhanced during central apneas [20,26], improves vagal tone and, consequently, reduces sympathetic cardiac outflow as well as heart rate variability [27,28]; reduces pulmonary capillary wedge pressure (PCWP), circulatory time [17], and chemoreceptor sensitivity [29]; and elevates baroreceptor sensitivity [28]. Elimination of the pathological breathing pattern may serve as the trigger for these changes, although the possibility that it is the CSA that causes the fall in LVEF is not proven since we found improved CSA in some patients but no change in LVEF. Additional effects that occur with PPV, but more impressive in the CPAP than bi-level ventilation depending on mean applied pressure, are an increase in intrathoracic pressure and a reduction of LV transmural pressure (LVPtm) [9,30]. With a decrease in LVPtm, there occurs a reduction of LV afterload and heart rate, stroke volume and cardiac output rise [9,30,31]. Furthermore, there seem to be some advantages of bi-level PPV in comparison to CPAP in patients with lower filling pressure on diuretics due to advantages for venous return and when applying it in patients with acute left ventricular failure for increasing and stabilizing functional residual capacity, improving pulmonary compliance and improving the ventilation– perfusion relationship in the presence of an elevated PCWP [32]. The described cardiopulmonary changes can lead to improvement of LV function, as we were able to measure. The reduction in LVPtm may, therefore, be the decisive mechanism in the long-term effects of PPV on LVEF, especially since the LVPtm effect can be observed among CHF patients, even in cases of effective medications for afterload reduction. It is important to note that blood pressure and heart rate in the daytime did not change under nocturnal PPV treatment in our patients. Similar data for CPAP treatment in CHF patients with OSA were reported earlier [28]. Few data are presently available on differentiation of the various PPV modes with respect to efficacy concerning CSR treatment and improvement of sleep. Publishing a comparison of CPAP and bi-level PPV, Ko¨hnlein et al. [17] came to the conclusion that both PPV techniques were equally effective for therapy of CSR and obstructive events, and for enhancement of sleep quality and of subjective sensation of health. Teschler et al. [16] tested three ventilation modes: bilevel ST ventilation, ASV, and CPAP. In contrast to oxygen therapy, all three techniques in the first night of therapy demonstrated significant effects on CSR, oxygen saturation, and arousals. Bi-level ventilation had

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more pronounced effects on sleep parameters. Our controlled therapy study describes the positive effect of PPV on CSR and respiratory-related arousal and a significant effect on quantitative sleep quality. Although we detected a significant decrease of respiratory-related arousals, there was a slight increase in the number of movement arousals (MAs), similar to obstructive sleep apnea syndrome [23]. Willson et al. [33] reported similar effects. Noda et al. [18] did not distinguish arousals and described a significant decrease in the overall number of arousals. Only a few short-term PPV studies reported an increase in total sleep time (TST), slow wave sleep and sleep efficacy and reduction in non-rapid eye movement (NREM) sleep stages 1 and 2 [16,33,17,34]. However, significant changes in sleep parameters have not been reported after long-term PPV therapy in previous studies [11,18]. Our patients, regardless of the PPV mode, received a full face mask. The mask prevents mouth leakage using low pressures, which can critically impair the comparison between different ventilation systems. Other authors used a nose mask with a chin strap [15] or provided no information on this aspect [11,16–18,20]. Our patients adapted relatively well to the ventilation therapy, despite a residual RDI of approximately 13.8 ± 13.2/h. Residual events are primarily due to periodic breathing among patients for whom the pressure has not yet been optimized. We tolerated residual periodic breathing, mainly among patients with compliance problems involving pressure increase. Our patients’ compliance rate of 4.8 h/night was similar to that reported by previous studies [11,17,20]. Compliance remains to be limited in patients with CHF. According to our results, bi-level ventilation is equally effective as ASV treatment, especially if the AHI under treatment is below 15/h. It should be noted, however, that out of nine patients without effective ventilation therapy seven had received bi-level S/T ventilation. An open question is whether the CHF patients who benefit from PPV in terms of a reduction of CSR also benefit over a longer treatment period in terms of outcome measures. In the clinical practice a bi-level S/T device may be as effective as an ASV or CPAP or auto-CPAP (APAP) device. To our knowledge, subjective compliance with any mode of ventilation is essential for the CHF patient in order to accept positive ventilation therapy at all. In order to reduce the high mortality in CHF patients with CSR, a treatment is really needed. That CPAP is effective to reduce mortality over time has been shown [8] but only in good ‘‘responders’’ to CPAP. Whether bi-level ventilation reduces mortality also still needs to be proven. In summary, therapy of CSR in CHF patients using any bi-level PPV (ASV or AutoSetCS) might be effective

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with respect to nocturnal central events and sleep quality, especially the arousal, and also improves LVEF. Furthermore, the bi-level PPV seems to be equal to or perhaps be more effective than CPAP treatment. Individual differences arise in this context, however, which in certain cases complicate practical application of this therapy to a particular patient. More studies are needed to better define the indications for PPV in CHF patients in order to evaluate the efficacy of the different modes of bi-level ventilation (ASV and AutoSetCS) and other modes (APAP and A-Flex). Studies are needed in particular to determine the prognostic value of PPV therapy in CHF patients with CSR.

[11]

[12]

[13]

[14]

[15]

Acknowledgement [16]

This study was supported in part by an unrestricted grant from Resmed, Germany. [17]

References [18] [1] Hanly PJ, Zuberi-Khokhar NS. Increased mortality associated with Cheyne-Stokes respiration in patients with congestive heart failure. Am J Respir Crit Care Med 1996;153(1):272–6. [2] Pepin JL, Couri-Pontarollo N, Tamisier R, Levy P. CheyneStokes respiration with central sleep apnoea in chronic heart failure: proposals for a diagnostic and therapeutic strategy. Sleep Med Rev 2006;10(1):33–47. [3] Sin DD, Logan AG, Fitzgerald FS, Liu PP, Bradley TD. Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration. Circulation 2000;102(1):61–6. [4] Lanfranchi PA, Somers VK, Braghiroli A, Corra U, Eleuteri E, Giannuzzi P. Central sleep apnea in left ventricular dysfunction: prevalence and implications for arrhythmic risk. Circulation 2003;107(5):727–32. [5] Krachman SL, Nugent T, Crocetti J, D’Alonzo GE, Chatila W. Effects of oxygen therapy on left ventricular function in patients with Cheyne-Stokes respiration and congestive heart failure. J Clin Sleep Med 2005;1(3):271–6. [6] Bradley TD, Holloway RM, McLaughlin PR, Ross BL, Walters J, Liu PP. Cardiac output response to continuous positive airway pressure in congestive heart failure. Am Rev Respir Dis 1992;145(2 Pt 1):377–82. [7] Naughton MT, Benard DC, Rutherford R, Bradley TD. Effect of continuous positive airway pressure on central sleep apnea and nocturnal PCO2 in heart failure. Am J Respir Crit Care Med 1994;150(6 Pt 1):1598–604. [8] Arzt M, Floras JS, Logan AG, Kimoff RJ, Series F, Morrison D, et al. 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 2007;115(25):3173–80. [9] Naughton MT, Rahman MA, Hara K, Floras JS, Bradley TD. Effect of continuous positive airway pressure on intrathoracic and left ventricular transmural pressures in patients with congestive heart failure. Circulation 1995;91(6):1725–31. [10] Mansfield DR, Gollogly NC, Kaye DM, Richardson M, Bergin P, Naughton MT. Controlled trial of continuous positive airway

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

pressure in obstructive sleep apnea and heart failure. Am J Respir Crit Care Med 2004;169(3):361–6. Kaneko Y, Floras JS, Usui K, Plante J, Tkacova R, Kubo T, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med 2003;348(13):1233–41. Bradley TD, Logan AG, Kimoff RJ, Series F, Morrison D, Ferguson K, et al. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005;353(19):2025–33. Javaheri S. CPAP should not be used for central sleep apnea in congestive heart failure patients. J Clin Sleep Med 2006;2(4):399–402. Kasai T, Narui K, Dohi T, Ishiwata S, Yoshimura K, Nishiyama S, et al. Efficacy of nasal bi-level positive airway pressure in congestive heart failure patients with Cheyne-Stokes respiration and central sleep apnea. Circ J 2005;69(8):913–21. Willson GN, Wilcox I, Piper AJ, Flynn WE, Norman M, Grunstein RR, et al. Noninvasive pressure preset ventilation for the treatment of Cheyne-Stokes respiration during sleep. Eur Respir J 2001;17(6):1250–7. Teschler H, Dohring J, Wang YM, Berthon-Jones M. Adaptive pressure support servo-ventilation: a novel treatment for CheyneStokes respiration in heart failure. Am J Respir Crit Care Med 2001;164(4):614–9. Ko¨hnlein T, Welte T, Tan LB, Elliott MW. Assisted ventilation for heart failure patients with Cheyne-Stokes respiration. Eur Respir J 2002;20(4):934–41. Noda A, Izawa H, Asano H, Nakata S, Hirashiki A, Murase Y, et al. Beneficial effect of bilevel positive airway pressure on left ventricular function in ambulatory patients with idiopathic dilated cardiomyopathy and central sleep apnea–hypopnea. Chest 2007;131:1694–701. Philippe C, Stoica-Herman M, Drouot X, Raffestin B, Escourrou P, Hittinger L, et al. Compliance with and effectiveness of adaptive servoventilation versus continuous positive airway pressure in the treatment of Cheyne-Stokes respiration in heart failure over a six month period. Heart 2006;92(3):337–42. Pepperell JC, Maskell NA, Jones DR, Langford-Wiley BA, Crosthwaite N, Stradling JR, et al. A randomized controlled trial of adaptive ventilation for Cheyne-Stokes breathing in heart failure. Am J Respir Crit Care Med 2003;168(9):1109–14. Hense HW, Koivisto AM, Kuulasmaa K, Zaborskis A, Kupsc W, Tuomilehto J. Assessment of blood pressure measurement quality in the baseline surveys of the WHO MONICA project. J Hum Hypertens 1995;9(12):935–46. Rechtschaffen A, Kales A, Berger RJ, Dement WC, Jacobsen A, Johnson LC et al. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Washington, DC: Public Health Service, U.S. Government, Printing Office; 1968. Fietze I, Quispe-Bravo S, Hansch T, Rottig J, Baumann G, Witt C. Arousals and sleep stages in patients with obstructive sleep apnoea syndrome: changes under nCPAP treatment. J Sleep Res 1997;6(2):128–33. Bradley TD, Takasaki Y, Orr D, Popkin J, Liu P, Rutherford R. Sleep apnea in patients with left ventricular dysfunction: beneficial effects of nasal CPAP. Prog Clin Biol Res 1990;345:363–8. discussion 368–70.:363–8. Naughton MT, Liu PP, Bernard DC, Goldstein RS, Bradley TD. Treatment of congestive heart failure and Cheyne-Stokes respiration during sleep by continuous positive airway pressure. Am J Respir Crit Care Med 1995;151(1):92–7. van-de-Borne P, Oren R, Abouassaly C, Anderson E, Somers VK. Effect of Cheyne-Stokes respiration on muscle sympathetic nerve activity in severe congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1998;81(4):432–6.

I. Fietze et al. / Sleep Medicine 9 (2008) 652–659 [27] Butler GC, Naughton MT, Rahman MA, Bradley TD, Floras JS. Continuous positive airway pressure increases heart rate variability in congestive heart failure. J Am Coll Cardiol 1995;25(3):672–9. [28] Tkacova R, Dajani HR, Rankin F, Fitzgerald FS, Floras JS, Douglas BT. Continuous positive airway pressure improves nocturnal baroreflex sensitivity of patients with heart failure and obstructive sleep apnea. J Hypertens 2000;18(9):1257–62. [29] Ponikowski P, Chua TP, Anker SD, Francis DP, Doehner W, Banasiak W, et al. Peripheral chemoreceptor hypersensitivity: an ominous sign in patients with chronic heart failure. Circulation 2001;104(5):544–9. [30] Tkacova R, Rankin F, Fitzgerald FS, Floras JS, Bradley TD. Effects of continuous positive airway pressure on obstructive sleep apnea and left ventricular afterload in patients with heart failure. Circulation 1998;98(21):2269–75.

659

[31] Granton JT, Naughton MT, Benard DC, Liu PP, Goldstein RS, Bradley TD. CPAP improves inspiratory muscle strength in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med 1996;153(1):277–82. [32] Shapiro BA, Kacmarek RM, Cane RD, et al. Pulmonary edema: part VII; Special considerations. In: Lampert R, Marshall D, editors. Clinical application of respiratory care, 4th ed.. St. Louis, MO: Mosby-Year Book; 1991. p. 87–392. [33] Willson GN, Wilcox I, Piper AJ, Flynn WE, Grunstein RR, Sullivan CE. Treatment of central sleep apnoea in congestive heart failure with nasal ventilation. Thorax 1998;53(Suppl. ):S41–6. [34] Reeves-Hoche MK, Hudgel DW, Meck R, Witteman R, Ross A, Zwillich CW. Continuous versus bilevel positive airway pressure for obstructive sleep apnea. Am J Respir Crit Care Med 1995;151(2 Pt. 1):443–9.