Trilevel adaptive servoventilation for the treatment of central and mixed sleep apnea in chronic heart failure patients Academic research paper on "Medical engineering"

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Sleep Medicine

journal homepage: www.elsevier.com/locate/sleep

Original Article

Trilevel adaptive servoventilation for the treatment of central and mixed sleep apnea in chronic heart failure patients

Olaf Oldenburg a'*, Thomas Bitter a, Birgit Wellmann b, Thomas Fischbach a, Christina Efkena, Anke Schmidtb, Dieter Horstkotte a

a Dept. of Cardiology, Heart and Diabetes Centre North Rhine Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany b Cardiac Research Unit, Heart and Diabetes Centre North Rhine Westphalia, Ruhr University Bochum, Bad Oeynhausen, Germany

ARTICLE INFO

Article history:

Received 20 June 2012

Received in revised form 12 December 2012

Accepted 15 December 2012

Available online 1 March 2013

Keywords:

Adaptive servoventilation Heart failure

Sleep-disordered breathing Cheyne-Stokes respiration Mixed sleep apnea Positive airway pressure therapy

ABSTRACT

Background: Sleep-disordered breathing (SDB) in patients with heart failure (HF) is of major prognostic impact, though treatment of simultaneously occurring central and mixed apnea events is challenging. The objective was to examine long-term effects of a new trilevel adaptive servoventilation (ASV) therapy in patients with systolic or diastolic HF.

Methods: A total of 45 consecutive patients with a history of HF, elevated N-termina l prohormone of brain natriuretic peptide levels, objective signs of cardiac dysfunction, and moderate to severe SDB (apnea-hypopnea index [AHI] p15/h) with combined central and mixed respiratory events were included in this study and ASV therapy (SOMNOvent CR, Weinmann) was offered. Results: In 38 patients (84%), ASV therapy was successfully initiated, with 23 (51%) patients showing appropriate compliance (device use p4 h/night for P5d/w) after 3.6 ±1.2 months. In these patients ASV therapy and HF status were re-evaluated. A sustained reduction was achieved in AHI (42.8 ± 17.5/ h vs 8.9 ± 5.8/h; p < 0.001) and oxygen saturation. Improvements also were recorded in New York Heart Association (NYHA) functional class (2.4 ± 0.5-1.9 ± 0.4; p < 0.001) and oxygen uptake during cardiopulmonary exercise testing (VO2 peak, 13.64 ± 3.5-15.8 ± 5.8 ml/kg/min; p < 0.002).

Conclusion: In selected HF patients, trilevel ASV therapy is able to treat SDB with combined central and mixed respiratory events. This treatment is associated with an improvement in HF symptoms and objective cardiopulmonary performance.

© 2013 Elsevier B.V. All rights reserved.

1. Introduction

A remarkably high prevalence of sleep-disordered breathing (SDB) has been observed in heart failure (HF) patients. Independent of the type of underlying cardiac disease, systolic or diastolic dysfunction, large scale studies revealed a prevalence of SDB between 69% and 76% [1,2]. Central sleep apnea with Cheyne-Stokes respiration (CSR) is characterized by recurrent central apneas alternating with a crescendo-decrescendo pattern of tidal volume [3,4]. CSR often is observed in non-REM sleep stages 1 and 2 and is associated with hyperventilation, apnea-related oxygen desaturations, increased sympathetic nerve activity, circulatory delay, and reduced blood gas buffering capacity [5-9]. In HF patients, SDB in general and CSR in particular are supposed to be associated with increased mortality [10,11].

* Corresponding author. Address: Dept. of Cardiology, Heart and Diabetes Centre North Rhine-Westphalia, Ruhr University Bochum, Georgstrasse 11, D-32545 Bad Oeynhausen, Germany. Tel.: +49 5731 97 1258; fax: +49 5731 97 2194. E-mail address: akleemeyer@hdz-nrw.de (O. Oldenburg).

1389-9457/$ - see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016Zj.sleep.2012.12.013

Although initial results with continuous positive airway pressure (CPAP) therapy to treat CSR were promising [12], the subsequent CANPAP (CANadian continuous Positive Airway Pressure) trial failed to show a positive impact on mortality in CPAP-treated HF patients with CSR [13]. Despite an improvement in nocturnal oxygenation, lowered norepinephrine plasma levels, and better performance in six-minute walking tests, mortality was not improved [13]. A later post hoc analysis of this trial demonstrated a benefit to transplant-free survival in patients with effective suppression of respiratory events with CPAP therapy [14].

Adaptive servoventilation (ASV) therapy is the latest method of ventilator support, specially designed to treat CSR in HF patients. ASV restabilizes CSR by applying anticyclic pressure support in phases of cyclic breathing [15]. The acute effects of different therapeutic options including oxygen, CPAP, bilevel, and ASV were compared in a one-night study of HF patients with CSR. All types of treatment were able to reduce central events and arousal activity to some degree but ASV was most effective [16,17]. The superiority of ASV to CPAP in reducing the apnea-hypopnea index (AHI) in Cheyne-Stokes breathing was verified in further clinical studies [18,20].

Our study aimed to investigate the effects of a new trilevel ASV device on respiratory and cardiac parameters in a cohort of patients with systolic or diastolic HF and nocturnal CSR with concomitant mixed apneic events.

2. Methods

2.1. Patients

From 03/2009 to 12/2010 a total of 45 patients with HF caused by systolic or diastolic dysfunction and moderate to severe SDB with central and mixed sleep apnea were consecutively included in our study. All patients were referred to the Heart and Diabetes Center North Rhine Westphalia for diagnosis and treatment of SDB. Diagnosis of HF was based on typical clinical signs and symptoms of HF (New York Heart Association [NYHA] functional class p II, elevated N-terminal prohormone of brain natriuretic peptide concentrations), with either reduced left ventricular ejection fraction (LVEF)( 6 45%) or with diastolic dysfunction as specified by European Society of Cardiology guidelines [21,22]. The study was approved by our local ethics committee.

2.2. Polysomnography

Overnight in hospital-attended polysomnography (PSG) according to the 2007 guidelines of the American Academy of Sleep Medicine was performed during a diagnostic night, as well as during ASV therapy initiation and follow-up [23]. PSG recordings including arousal analyses were independently analyzed (T.F., C.E.). For study enrollment, a patient's PSG recordings had to reveal a moderate to severe SDB (AHI p 15/h) with a majority of central and mixed apneic events and less than 20% of events scored as being obstructive.

2.3. Trilevel adaptive servoventilation

Trilevel adaptive servoventilation (SOMNOvent CR, Weinmann, Hamburg, Germany) uses three different pressure levels over the course of the breathing cycle (Fig. 1). The inspiratory positive airway pressure (IPAP) pressure provides the inspiratory splint and ventilation. Maximal IPAP can be increased up to 20-hour Pa. Expiratory pressure is varied between a lower level at the start of expiration expiratory positive airway pressure and a higher level at the

end of expiration end-expiratory positive airway pressure. The regulation of the device is based on flow, pressure, and snoring signals. For each breath, current minute ventilation is measured and compared to the patient's average respiratory minute ventilation. The algorithm is aimed at damping the respiratory instability in CSR and restoring stable breathing.

2.4. ASV therapy initiation

PSG recordings were explained to each patient individually and ASV treatment was offered to every patient. Mask fitting and ASV testing were done in the afternoon and included blood pressure, heart rate and leakage monitoring and close clinical observations. In patients consenting to further treatment, ASV was individually titrated during the following night with PSG surveillance. The next morning PSG results were analyzed independently (T.F.) and long-term treatment was initiated if patients agreed to further treatment and AHI was 610/h or 650% of baseline.

2.5. Follow-up

Follow-up was scheduled three months later and included overnight PSG on ASV treatment, compliance check based on device stored data, clinical examination, vital signs, capillary blood gas analysis and cardiopulmonary exercise testing. Appropriate compliance/adherence to therapy was defined as using the device p four hours per night for p five days a week.

2.6. Cardiopulmonary exercise testing

Symptom-limited bicycle exercise testing with spirometry (CPX) was used to determine exercise tolerance and oxygen uptake. Exercise testing started with a workload of 10 watts, continuously increasing by 10 watts every minute. Maximum workload and peak oxygen consumption were recorded, and predicted VO2 peak was automatically calculated, considering patients' gender and age. Patient's individual aerobic-anaerobic threshold and VE/ VCO2 slope were determined.

2.7. Statistical methods

All data analysis was performed using SigmaPlot™ Software (Version 11.0, Systat, Germany). In continuous data, paired t test

or Wilcoxon signed rank test were used to determine differences before and after treatment. Analysis of variance with Tukey post hoc analysis was used for repeated measures. For nominal variables v2 testing was performed. A value of p < 0.05 was considered significant for all comparisons. Data are presented as mean ± standard deviation (SD) and/or median.

3. Results

Demographic and clinical data are presented in Table 1. Of the 45 patients initially included in our study, 38 patients were successfully treated by SOMNOvent® CR therapy (Fig. 2). Of the remaining seven patients, two patients refused therapy initiation and five patients were without appropriate immediate therapy results (AHI > 10/h or >50% of baseline AHI). Within the follow-up period a total of 17 patients (37.8%) refused or stopped (n = 9) the therapy, were noncompliant (n = 3), pending (n = 3), or were followed up elsewhere (n = 2). Twenty-six patients completed the follow-up, with 23 showing appropriate compliance with therapy.

In the 23 patients who fulfilled the criteria for the final assessment, a sustained reduction was achieved in AHI from baseline to initial ASV initiation (42.8 ± 17.5/h to 13.3 ± 12.0/h, p < 0.001) to long-term follow-up after 3.6 ±1.2 months (9.0 ± 5.9/h; p < 0.001; Fig. 2). Despite a clear decrease in respiratory events and improvement in oxygen saturation during the night, a uniform and clinically relevant improvement in sleep quantity and quality could not be ascertained (Table 2). In addition, there was no relevant decline in nocturia frequency (1.94 ± 1.0 per night to 1.89 ± 1.08 per night; p = not significant).

Regarding HF parameters, NYHA functional class improved from 2.4 ± 0.5 to 2.0 ± 0.4 (p < 0.001) and objective performance during CPX testing remarkably improved (Table 3). In addition, daytime PaCO2 increased from low-normal values to mid-normal values.

Table 1

Demographic and clinical data of all 45 patients (23 compliant patients with complete follow-up and 22 patients excluded from further analysis) included in the study.

Parameter All Compliant Excluded patients

Number of patients (n) 45(100%) 23 (51.1%) 22 (48.9%)

Age (y) 70.5 ± 9.5 71.1 ±9.3 69.8 ± 9.8

Men (n) 41 (91.1%) 20 (87.0%) 21 (95.5%)

BMI (kg/m2) 29.2 ± 5.5 29.2 ± 5.4 29.5 ± 5.4

Type of heart failure

Systolic (HF) 20 (44.4%) 8 (34.8%) 12 (54.5%)

Diastolic (HF) 25 (55.6%) 15 (65.2%) 10 (45.5%)

CAD (n) 29 (64.4%) 16 (70%) 13 (54.5%)

Diabetes mellitus (n) 20 (44.4%) 9 (39.1%) 11 (50.0%)

Hypertension (n) 42 (93.3%) 21 (91.3%) 21 (95.5%)

Blood pressure

systolic (mmHg) 120.3 ±20.8 118.0 ±22.5 122.8 ±19.0

diastolic (mmHg) 73.5 ±15.3 71.3 ±11.9 75.9 ±18.2

Heart rate (min-1) 70.1 ± 13.4 71.5 ±10.2 68.7 ±16.3

Rhythm

Sinus rhythm (n) 34 (75.6%) 19 (82.6%) 15 (68.2%)

Atrial fibrillation (n) 10 (22.2%) 3 (13.0%) 7 (31.8%)

Pacemaker (n) 1 (2.2%) 1 (4.4%) 0 (0%)

Medication

ACEI/ARB (n) 42 (93.3%) 21 (91.3%) 22 (100%)

ß blocker (n) 36 (80.0%) 17 (73.9%) 19 (86.4%)

Diuretics (n) 33 (73.3%) 16 (61.5%) 17 (77.3%)

AldoAnta (n) 20 (44.4%) 10 (43.5%) 10 (45.5%)

Digitalis (n) 7 (15.6%) 2 (8.8%) 5 (22.7%)

Amiodarone (n) 3 (6.7%) 0(0%) 3 (13.6%)

BMI, body mass index; HF, heart failure; CAD, coronary artery disease; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; AldoAnta, aldosterone antagonists.

There were no changes in medication within the cohort of the final 23 patients.

4. Discussion

In our prospective observational cohort study, we were able to show beneficial effects of a new Trilevel ASV device on respiratory and cardiac parameters in a selected cohort of HF patients with combined central and (Fig. 3) mixed sleep apnea. In patients with appropriate therapy response during therapy initiation and compliant to therapy, there was a sustained decrease in nocturnal apneas and hypopneas with increased oxygen saturations, an improvement in HF symptoms, and objective cardiopulmonary performance during exercise testing.

Results of the CANPAP trial and its post hoc analysis suggest that effective reduction in nocturnal respiratory events is essential to enable an improvement in cardiac function and the prognosis of HF patients with SDB and CSR. A residual AHI of 15 per hour seems to be inadequate to improve outcome of these HF patients [13,14]. Therefore, for the purpose of our study we aimed to reduce AHI to fewer than <10 per hour or at least to reduce the number of events by 50% within the first night. In HF patients with predominant CSR, ASV has been shown to be more efficient than oxygen, CPAP or bilevel positive airway pressure (PAP) within the first night of therapy [16,17]. These superior effects of ASV were confirmed after 6 months and 12 months by other (Fig. 4) studies using various devices [18-20]. The therapeutic efficacy and superiority of ASV vs CPAP with regard to nocturnal respiratory disturbances and certain cardiac parameters have been proven in different clinical studies, with respect to nocturnal breathing pattern [24], daytime sleepiness [25], and increase of LVEF after 6 months [18]. Thus, the challenge of our study was to treat CSR and coexisting obstructive or mixed respiratory events.

The SOMNOvent ASV algorithm is specially designed to treat these mixed respiratory events by reacting specifically to various types of respiratory events [26]. In cases of typical CSR, ASV offers anticyclic modulated ventilation to counteract the waning and waxing of respiration during episodes of periodic breathing, while delivering mandatory ventilator support during central apneas. Coexisting obstructive events, which are prone to emerge during the end of expiration [27,28], are depressed by an auto regulated end-expiratory pressure support to keep airways open. With the use of this new algorithm, central, obstructive, or mixed apneic events were successfully treated in a single night. Remaining respiratory events were mainly hypopneas but oxygen saturation remarkably improved.

Despite altered sleep architecture with reduced sleep efficiency and quality, HF patients do not report SDB-specific symptoms [29,30]. Symptoms include more paroxysmal nocturnal dyspnea, insomnia, and fatigue rather than symptoms associated with daytime sleepiness. As in other pilot studies on ASV treatment in HF patients, we were not able to show notable improvement in sleep efficiency and quality [31]. In addition, ArI was comparably low at baseline and did not change with ASV treatment. This finding is in close agreement with results of the CANPAP-trial. Besides a remarkable decrease in AHI, ArI, and sleep architecture did not change [32]. Even after successful cardiac transplantation, ArI or sleep structure might not change [33] indicating that arousals may exist more or less independently of underlying CSR or HF [32] failure. However, a recent study on acute effects of nocturnal oxygen or ASV has shown a significant decrease within a single night of treatment [34]. A final answer, if there is one, will probably require a large randomized cohort and a longer follow-up, these analyses possibly are part of ongoing large-scale randomized controlled trials (RCTs) like SERVE-HF or ADVENT-HF.

Fig. 2. Study flow chart. 45 heart failure patients with normal (HFNEF) or reduced ejection fraction (HFREF) with moderate to severe central sleep apnea (CSA) or mixed sleep apnea (mixSA) were included in our study. Successful therapy initiation was possible in 38 patients (84.4%). Of those, 26 patients (68.4%) completed a follow-up (FU) after 3.6 ± 1.2 months, with 23 (60.5%) having appropriate compliance with therapy. From enrollment to FU a total of 17 (37.8%) patients refused or stopped therapy or were noncompliant, while in five patients FU was pending or done elsewhere. Data from these patients* were excluded from further analysis.

Table 2

Polysomnographic parameters of 23 compliant patients at baseline and follow-up. There was a uniform and robust decrease in respiratory events and improvement in oxygen saturation during the night, in which there were no relevant change in sleep quantity and quality.

Parameter Baseline Follow-up P value

TST (min) 376 ±58 340.0 ±65.5 0.082

WASO (min) 44 ±37 50.3 ±41 0.557

N 1 (%) 12.1 ±11.6 18.8 ±15.1 0.075

N 2 (%) 47.0 ±13.1 39.0 ±13.7 0.031

N 3 (%) 29.2 ±11.8 28.1 ±9.6 0.799

REM (%) 11.7 ± 6.3 12.9 ±8.1 0.634

AHI (h-1) 42.8 ± 17.5 8.9 ±5.8 0.001

AI (h-1) 26.6 ± 1.3 0.7 ±0.9 0.001

oAI (h-1) 10.2 ± 12.9 0.2 ±0.3 0.001

cAI h-1 10.4 ± 12.0 0.3 ±0.6 0.001

mAI (h-1) 6.4 ± 8.0 0.2 ±0.6 0.001

HI (h-1) 16.2 ± 9.5 8.2 ±5.3 0.003

Mean SaO2 (%) 91.9 ± 2.7 93.9 ±1.7 0.001

Minimum SaO2 (%) 79.0 ± 5.7 83.7 ± 8.4 0.019

Mean O2 desaturation (%) 7.0 ±3.3 4.2 ±0.9 0.001

ArI (h-1) 9.4 ± 4.3 7.7 ±4.8 0.567

TST, total sleep time; WASO, wake after sleep onset; REM, rapid eye movement sleep; AHI, apnea-hypopnea index; AI, apnea index; oAI, obstructive apnea index; cAI, central apnea index; mAI, mixed apnea index; SaO2, oxygen saturation in pulse oximetry; ArI, arousal index.

Previous studies have documented a significant improvement in NYHA class, decrease in natriuretic peptide concentrations, improvement in LVEF, and enhanced cardiopulmonary performance. These studies were performed in HF patients with impaired (systolic HF) or preserved (diastolic HF) LVEF and predominant CSR without considerable obstructive or mixed respiratory events [35— 37]. Thus, for the purpose of a pilot study investigating a new algorithm based on trilevel ASV, we included patients with systolic and diastolic HF but with more complex SDB. In this first study, trilevel ASV effectively treated respiratory events and improved HF symptoms and performance during cardiopulmonary exercise testing.

Table 3

In heart failure patients (New York Heart Association > II) trilevel ASV Therapy (SOMNOvent CR) efficiently treats nocturnal respiratory disturbances, improves clinical heart failure symptoms, increases objective cardiopulmonary performance and raises daytime pCO2 to mid-normal values.

Parameter Baseline Follow-up P value

NYHA functional class 2.4 ± 0.5 2.0 ± 0.4 0.001

Workload (watts) 84.3 ± 23.9 92.7 ± 33.8 0.199

VO2-AT (mmHg) 11.7 ±2.3 14.2 ± 5.0 0.048

Peak VO2 (mmHg) 13.6 ±3.5 15.8 ±5.8 0.020

Predicted VO2 peak (%) 61.4 ±14.8 69.8 ± 23.0 0.026

VE/VCO2 (slope) 36.0 ± 4.3 34.2 ± 5.3 0.110

PaCO2 (mmHg) 36.4 ± 3.1 37.9 ± 3.8 0.040

NYHA, New York Heart Association; AT, anaerobic threshold.

With ASV, NYHA functional class and oxygen uptake at the individual aerobic-anaerobic threshold as well as peak oxygen uptake and predicted peak oxygen uptake improved by a clinically relevant and statistically significant magnitude.

Chronic hyperventilation represents a clinical sign of impaired respiratory control in HF patients [6,7,15,37,38]. This hyperventilation can result in CSR while patient is asleep but can continue during the day while the patient is awake, as documented by a low PaCO2 (usually <38 mmHg) [39]. In our study, ASV was able to counteract hyperventilation as documented by a slight but significant increase in daytime PaCO2 and a trend towards a decrease in VE/VCO2 slope which is an indicator of central CO2-receptor sensitivity and marker of respiratory control (in)stability and prognosis in HF patients [38,40,41]. Further studies are warranted to confirm these effects and to analyze if this is a direct effect of ASV treatment on respiratory control or if stabilized respiration represents an indirect effect of improved cardiac and cardiopulmonary function.

PAP therapy is not tolerated by every patient [42]. Especially HF patients are sometimes very sensitive to PAP treatment. Thus, ASV

Apnea - HvpoDnea - Index Central Apnea Index

Baseline Initiation Follow-up Baseline Initiation Follow-up

Fig. 3. Apnea-hypopnea index and central apnea index significantly decreased from baseline to adaptive servoventilation therapy initiation and follow-up in patients with complete FU and compliant to therapy. (p < 0.05).

Fig. 4. Cardiorespiratory exercise testing results. There was a significant increase in oxygen uptake at the individual anaerobic threshold (AT) and peak oxygen uptake (peak VO2) from baseline to follow-up.

was especially designed to use the lowest end-expiratory pressure and most comfortable inspiratory pressure support. ASV is preferred to all other PAP therapy modalities [16] but still requires a mask and overcoming resistance to therapy daily, particularly in patients who do not perceive an immediate subjective benefit. In our study a total of 20% of patients rejected ASV treatment from first offer to follow-up after three months. In previous studies using a different ASV device, we documented an initial rejection rate at therapy initiation of 15.7%, followed by an additional 17.6% within the first six months of therapy. However, until more recently and until invasive therapy options (eg, transvenous phrenic nerve stimulation) [43] have shown long-term therapeutic benefit, ASV treatment represents the gold standard of CSR treatment in HF patients.

Finally our clinical study showed that HF patients with confounded types of SDB including central and mixed events may benefit from trilevel ASV with respect to nocturnal respiratory disturbances, cardiopulmonary performance, and clinical symptoms. Further studies are needed to examine if these improvements result in an increase in quality of life, fewer HF-associated hospital admissions, and a positive impact on mortality.

5. Limitations

Our study was designed as an observational pilot study to investigate the effects of a new ASV algorithm in HF patients with a challenging type of SDB. Positive effects on nocturnal respiratory effects have been shown in a highly selected cohort of patients with good initial therapy response and adherent to long-term therapy. Thus, there are a non negligible number of patients without appropriate initial therapy response, emphasizing the need for an RCT. Two large-scale multicenter RCTs currently are investigating the effects of ASV on mortality and hospitalization in patients with systolic HF. The Treatment of Predominant Central Sleep Apnoea by Adaptive Servo Ventilation in Patients with Heart Failure (Serve-HF) study (ClinicalTrials.gov Identifier: NCT00733343) is expected to answer this question by 2015. The second RCT (ADVENT-HF) investigates the Effects of Adaptive Servo Ventilation (ASV) on Survival and Hospital Admission in Heart Failure independent of a predominance of central or obstructive respiratory events (ClinicalTrials.gov Identifier: NCT01128816). However, none of these studies are using the device used in our study and none are investigating the effects on diastolic HF.

6. Conclusion

In selected HF patients trilevel ASV therapy is able to treat even challenging SDB with combined central and mixed respiratory events. This treatment is associated with an improvement in HF symptoms and in objective cardiopulmonary performance. The possible influence on quality of life and the prognostic value of trilevel ASV therapy need to be determined in large RCTs. In fact our pilot study does not allow generalized conclusions but represents a first step towards a better understanding of these challenging patients. Finally there is a need for studies investigating the role of SDB in diastolic HF including the effects of SDB treatment in these patients.

Conflict of interest

The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2012.12.013.

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