Effectiveness of Adaptive Servo Ventilation in the treatment of hypocapnic central sleep apnea of various etiologies

Sleep Medicine 12 (2011) 952–958

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

Original Article

Effectiveness of Adaptive Servo Ventilation in the treatment of hypocapnic central sleep apnea of various etiologies Claudio Carnevale a,b,d, Marjolaine Georges c, Claudio Rabec c, Renaud Tamisier a,b, Patrick Levy a,b,1, Jean-Louis Pépin a,b,1,⇑ a

INSERM U1042, Laboratoire HP2, Université Joseph Fourier, Faculté de Médecine, 38700 Grenoble, France Pôle Rééducation et Physiologie, CHU, 38043 Grenoble, France Service de Pneumologie et Réanimation Respiratoire, Centre Hospitalier et Universitaire de Dijon, Dijon, France d Dipartimento Toraco-Polmonare e Cardio-Circolatorio, University of Milan, IRCCS Fondazione Cà Granda, Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy b c

a r t i c l e

i n f o

Article history: Received 12 November 2010 Received in revised form 4 July 2011 Accepted 6 July 2011 Available online 24 October 2011 Keywords: Central sleep apnea Treatment Adaptive Servo Ventilation Chronic heart failure Complex sleep apnea Control of breathing

a b s t r a c t Background: Central sleep apnea (CSA) occurs in clinical situations that induce hypocapnia and respiratory instability during sleep. This is true, not only in heart failure patients, but also in patients suffering from neurological diseases and idiopathic CSA. Adaptive Servo Ventilation (ASV) is frequently prescribed in France for the treatment of CSA, but only a few studies have evaluated ASV treatment with regards to long term effectiveness and compliance. Methods: Retrospective chart review in two French centers of the outcome of 74 CSA patients treated by ASV with a mean follow up on ASV of 36 ± 18 months. Results: Thirty-three of the 74 patients suffered from CSA related to heart failure (HF), whereas the 41 others exhibited CSA mainly associated with neurological disorders or idiopathic CSA. Mean ASV compliance was 5.2 ± 2.6 and 5.9 ± 2.9 h per night in cardiac failure and non-cardiac failure patients, respectively. All patients significantly improved their apnea + hypopnea index (from 47.4 ± 19.8 to 6.9 ± 9.3/h [p < 0.001]) and mean nocturnal SaO2 (from 92.1 ± 2.6% to 93.6 ± 3.2% [p < 0.001]). The Epworth sleepiness scale score was reduced from 10.2 ± 5.2 to 6.5 ± 3.9 (p < 0.01) in compliant patients but not in non-compliant patients (less than 3 h per night). Moreover, compliant cardiac failure patients demonstrated a significant improvement in their NYHA score [p < 0.05]. Lastly, ASV significantly reduced chronic hyperventilation as assessed by blood gases. Conclusion: Our findings suggest that ASV is well tolerated and effective for most patients with hypocapnic central sleep apnea and chronic hyperventilation. Ó 2011 Elsevier B.V. All rights reserved.

1. Introduction The pathophysiology and the prevalence of the various forms of central sleep apnea (CSA) vary greatly [1]. In clinical practice, two main categories of central sleep apnea can be distinguished by diurnal blood gases and chemosensitivity. Patients with blunted chemosensitivity exhibit daytime hypercapnia and then, during sleep, the removal of the wakefulness drive worsens hypercapnia

Abbreviations: AHI, apnea + hypopnea index; ASV, Adaptive Servo Ventilation; CHF, chronic heart failure; CompSAS, complex sleep apnea; CPAP, continuous positive airway pressure; CSA, central sleep apnea; CSA/CSR, central sleep apnea and Cheyne–Stokes respiration; HF, heart failure; LVEF, left ventricular ejection fraction. ⇑ Corresponding author. Address: Sleep Laboratory and EFCR, Grenoble University Hospital, BP 217, 38043 Grenoble Cedex 09, France. Tel.: +33 4 76 76 55 16; fax: +33 4 76 76 55 86. E-mail address: [email protected] (J.-L. Pépin). 1 Patrick Levy and Jean-Louis Pépin are co-senior authors. 1389-9457/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2011.07.008

leading to hypercapnic CSA. On the opposite end of the spectrum are hypocapnic CSA patients with a PaCO2 close to the apneic threshold [2]. In these subjects, respiratory control system instability is characterized by elevated hypercapnic ventilatory responses leading to daytime hypocapnia. During sleep, any arousal will result in a ventilatory overshoot because of exaggerated ventilatory responses. PaCO2 then decreases and crosses the apnea threshold leading to central respiratory events inducing micro-arousals and, thus, to the perpetuation of breathing instability. These are the important pathophysiological traits occurring in CSA associated with chronic cardiac failure (CHF) [3], but also with idiopathic CSA [4] and some neurological disorders [5]. Sleep breathing disorders occur commonly in CHF patients and seem to be associated with deterioration in cardiac function and potentially with increased mortality [6–8]. Approximately one third of CHF patients present with CSA and Cheyne–Stokes respiration (CSA/CSR), one third with obstructive sleep apnea, and the others are free of sleep breathing disorders [9]. Cardiac failure

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and the resulting pulmonary congestion activate lung vagal irritant receptors, thus leading to hyperventilation, hypocapnia, and CSA [3]. Continuous positive airway pressure (CPAP) has been proposed to suppress CSA/CSR and improve prognosis in CHF patients. Open studies or small randomized controlled trials suggest that CPAP use over 1–3 months alleviates CSA–CSR [10,11], increases LVEF [12], and reduces adrenergic tone [13]. CPAP stabilizes ventilation by improving cardiovascular function and the added dead space elevates PaCO2. The CANPAP trial, the first large scale randomized controlled trial treating CHF patients by CPAP, did not confirm any reduction in mortality [14]. Nevertheless, a post hoc analysis demonstrated a significant improvement in mortality in the subgroup of the CSA–CSR population effectively treated by CPAP when compared to CPAP-non-responders [15]. Adaptive Servo Ventilation (ASV) may be more effective on central sleep respiratory disturbances than CPAP and associated with a higher rate of long term compliance [16]. ASV delivered in the present study by AutoSet CS™2 provides baseline ventilatory support in addition to a fixed end-expiratory pressure and a default back-up rate of 15 breaths/min. Depending on the setting, inspiratory pressure servo-adapts in order to maintain ventilation at 90% of a running 3-min reference period. The inspiratory pressure will increase or decrease in mirror of patient respiratory efforts to avoid ventilatory instability. Thus, as CPAP, ASV increases overnight PaCO2 [17] and stabilizes ventilation by eliminating apneas and hypopneas [16–18], but may have a lesser impact on intra thoracic hemodynamics. ASV is the first line of treatment for sleep breathing disorder in CHF patients [16–18], but has also been suggested as potentially effective in other causes of CSA such as stroke or other neurological diseases, in patients chronically treated with opioids [19], and in patients suffering from idiopathic CSA breathing [20]. Apart from studies in CHF, previous reports are small case series and very few studies have evaluated ASV treatment in terms of feasibility, effectiveness, and compliance in clinical cohorts [21]. The aim of our study was to evaluate clinical outcomes and long term compliance in a real life, large cohort of patients using ASV for CHF-related CSA as well as hypocapnic CSA from other causes. 2. Material and methods 2.1. Patients We identified consecutive patients who were referred to initiate ASV at two university hospitals in France (Dijon and Grenoble). All patients had undergone prior polysomnography or respiratory polygraphy showing central sleep apnea. ASV was considered the best treatment option by the clinicians participating in the study in two circumstances: (1) CHF patients with CSA, as the CANPAP study has shown that CPAP can be deleterious in some sub-groups and published data indicating that ASV is more effective and better tolerated [14,16] (2) CSA associated with neurological diseases or considered as idiopathic. CPAP is generally not effective in this situation. 2.2. Definitions An apnea was defined as a complete cessation of airflow for at least 10 s and a hypopnea as a reduction of at least 50% in the nasal pressure signal or a decrease between 30% and 50% associated with either oxygen desaturation of at least 3% or an EEG arousal [22], both lasting for at least 10 s. Apneas were classified as obstructive, central, or mixed according to the presence or absence of respiratory efforts. The classification of hypopneas as obstructive or

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central was based on the thoraco-abdominal band signal and the shape of the respiratory curve of nasal pressure (flow limited aspect or not) [23]. Central sleep apnea (CSA) was diagnosed if the number of respiratory events per hour was P15 and at least 50% of the total AHI was central in origin [14]. 2.3. Study design Medical charts were reviewed and demographic, NYHA status, if relevant, clinical, blood gases, and polygraphic/polysomnographic data were extracted. Except for cases of complex sleep apnea, central apneas were seen on the initial diagnostic polysomnogram. Available information included in the ventilatory support device data (index of residual events, level of leaks), compliance and treatment withdrawals were collected. This protocol was reviewed and approved by the Institutional Review Board of Grenoble University Hospital. 2.4. Outcomes Effect of ASV in reducing abnormal respiratory events during sleep, compliance, changes in blood gases, and symptoms were gathered from the follow-up records in the different CSA subgroups. Since, in France, treatment reimbursement is contingent upon a use of at least 3 h per night, we used this arbitrary threshold to separate compliant and non-compliant patients. Predictors for good compliance were identified. 2.5. Statistical methods Unpaired t tests and Mann–Whitney U tests were used depending on the normality of data distribution. Results are mean ± SD. p Values <0.05 were considered statistically significant. 3. Results 3.1. Study population Between 01/01/2001 and 30/06/2007, a series of 121 patients had been diagnosed for CSA and subsequently treated by ASV in both centers. Reliable data were available and analyzed for 74 patients (mean follow up of 36 ± 18 months). At baseline, characteristics of the 47 excluded patients without complete follow-up data did not differ from the study group, except for diastolic blood pressure (74 ± 13 mmHg vs 80 ± 12, p < 0.02, respectively). Before initiating ASV, 18 of the 74 patients were unsuccessfully tested with CPAP (n = 14), CPAP + oxygen (n = 1), nocturnal oxygen therapy (n = 2), and Bilevel ST (n = 1). Table 1 shows anthropometric data, severity of CSA, and arterial blood gas characteristics at baseline. For the whole group, total AHI was 53 ± 23.8/h with a percentage of central events above 50% and a mean value for obstructive and mixed apneas of 14.6 ± 20.6/h. CSA was related to CHF in 33 patients and idiopathic or associated with a neurological disorder in the remaining 41 (nine with a stroke history, five with complex sleep apnea [CompSAS], one with Charcot Marie Tooth disease, one with myotonic dystrophy, one with Parkinson’s disease, two with pulmonary hypertension, one with narcolepsy + CSA, and 21 with idiopathic CSA). Compared to others, patients with CHF-related CSA were significantly older, less sleepy, and exhibited a lower mean nocturnal SaO2. 3.2. ASV settings and compliance The mean expiratory positive airway pressure was set at 6 ± 1 cm H2O. Default settings (inspiratory pressure increases

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Table 1 Patient baseline characteristics. Variable

Whole group (n = 74)

Non-CHF (n = 41)

CHF (n = 33)

p Value

Anthropometric data Age (years) Male/female gender (number) BMI (kg/m2)

64 ± 14 67/7 30.2 ± 4.9

60 ± 14 37/4 30.3 ± 5.5

69 ± 11 30/3 30 ± 4.2

0.002** NS 0.4

Sleep respiratory disturbance parameters AHI (number/hour of recording) Mean nocturnal SaO2 (%) Minimal nocturnal SaO2 (%) Epworth sleepiness scale score (ESS)

53.0 ± 23.8 92.1 ± 2.6 78.4 ± 10.6 8.9 ± 5.3

52.2 ± 23.9 92.5 ± 2.4 79.3 ± 9.9 10.7 ± 5.3

54.0 ± 24.0 91.5 ± 2.6 77.2 ± 11.3 6.8 ± 4.7

0.3 0.08 0.42 0.002

Hemodynamic parameters Clinical SBP (mmHg) Clinical DBP (mmHg) LVEF (%)

140 ± 20 80 ± 12 NA

139 ± 17 79 ± 12 NA

141 ± 23 81 ± 13 40.1 ± 13.5

0.3 0.2 –

Arterial blood gases PaCO2 (kPa) PaO2 (kPa)

4.8 ± 0.5 10.5 ± 2

4.9 ± 0.5 10.6 ± 2.1

4.7 ± 0.5 10.2 ± 1.7

0.2 0.2

Values are mean ± SD. BMI, body mass index; AHI, apnea + hypopnea index; SBP, systolic blood pressure; DBP, diastolic blood pressure; LVEF, left ventricular ejection fraction; NA, not available; NS, not significant. ** p < 0.01 for comparison between non-CHF and CHF subgroups.

ranging from a minimum of 3 cm H2O to a maximum of 10 cm H2O) were used. Fifty-six of the 74 patients (75.6%) were considered compliant as they used their device for more than 3 h per night. Compliance was 72.8% and 78% in CHF and non-CHF patients, respectively. The average number of hours of ASV daily use was 5.2 ± 2.6 and 5.9 ± 2.9 h in CHF and non-CHF patients, respectively. Table 2 shows baseline characteristics of compliant and non-compliant patients in the whole group and in the specific subgroups of CSA. High compliance was linked with older age and female gender.

3.5. Specific subgroups of CHF patients Compliant CHF patients using ASV showed a significant improvement of their NYHA status. Fifty percent of the compliant patients improved their NYHA class versus only 16.6% of the non-compliant patients (Fig. 2) (p < 0.05). In compliant CHF patients, LVEF increased by a mean of 2.57%, a much larger increase than in non-compliant CHF patients, which was only 1.5%. The comparison, however, did not reach statistical significance. 4. Discussion

3.3. ASV impact on sleep respiratory disturbances during sleep As shown in Fig. 1, ASV significantly reduced the apnea + hypopnea index (AHI) in the whole population from 53.0 ± 23.8 to 5.9 ± 8.0/h, p < 0.001. Accordingly, mean nocturnal SaO2 (from 92.1 ± 2.6% to 93.6 ± 3.2%, p < 0.01) and minimal nocturnal SaO2 (from 78.4 ± 10.6% to 85.3 ± 8.2%, p < 0.001) significantly increased. Time spent with an SaO2 below 90% also improved significantly compared to baseline (from 20.6 ± 23.3% to 8.2 ± 18.5% of recording time, p < 0.001). Importantly, ASV efficacy was the same in the two subgroups with or without CHF (Fig. 1).

Our study provides new data about ASV in a clinical, real-life situation. We demonstrated that this ventilatory mode was effective in suppressing abnormal respiratory events during sleep, not only in CHF, but also in idiopathic CSA and in hypocapnic CSA related to neurological diseases. With respect to underlying mechanisms of CSA, ASV also reduced chronic hyperventilation significantly. Sleepiness improved, particularly in non-CHF patients, whereas NYHA class recovered in CHF patients. Finally, the compliance rate was high, with more than 70% compliant patients, regardless of CSA etiology. 4.1. ASV: impact on sleep respiratory disturbances and sleepiness

3.4. Impact of ASV on daytime arterial blood gases and symptoms The mean/median delay for blood gases withdrawal was 7.3/ 1.5 months before ASV therapy initiation and 8.7/8.4 months after ASV initiation. ASV significantly increased PaCO2 in compliant patients from 4.82 ± 0.58 to 4.97 ± 0.55 kPa, p = 0.03 compared to 4.87 ± 0.45 to 5.05 ± 0.64, p = 0.24 in non-compliant patients. Chronic alkalosis was also improved in compliant (pH from 7.43 ± 0.02 to 7.42 ± 0.03, p < 0.001) but not in non-compliant patients (from 7.43 ± 0.02 to 7.43 ± 0.03, NS). Taken together, these results show that ASV reduced chronic hyperventilation. Self-reported daytime sleepiness assessed by the Epworth sleepiness scale was reduced from 10.2 ± 5.2 to 6.5 ± 3.9 (p < 0.01) in compliant patients but not in non-compliant patients (from 8.9 ± 6.7 to 7 ± 3.8, NS). As CHF patients were not sleepy at baseline (Table 1), this effect was mainly explained by the ESS reduction in the non-CHF subgroup.

In CHF patients, the ability of ASV to reduce central events has already been shown both in observational cohorts [17,24] and in small randomized controlled trials [16,18]. In the study by Philippe et al. [16], some patients who responded to CPAP after three months of treatment did not respond at six months, whereas the effectiveness of ASV was consistent over six months. A post hoc analysis of the CANPAP study [14] suggested that, in CHF patients, suppression of central sleep apnea by CPAP might improve survival [25]. However, CSA was suppressed in only half of the patients and this limited rate of response has been confirmed by later studies [26,27]. In a clinical practice setting, patients with cardiac failure could be treated first by CPAP and restudied after one month. If CPAP was effective in suppressing CSA, then it could be continued; if it was not effective then CPAP could be discontinued and patients treated by other forms of positive airway pressure (i.e., ASV), which might be more effective than CPAP [16,28]. This may represent the most cost-effective way to treat these patients. This question is

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C. Carnevale et al. / Sleep Medicine 12 (2011) 952–958 Table 2 Baseline characteristics of patients with respect to ASV compliance. Variable

Whole group

Non-CHF patients

CHF patients

Daily compliance >3 h (n = 56)

Daily compliance <3 h (n = 18)

p Value

Daily compliance >3 h (n = 32)

Daily compliance <3 h (n = 9)

p Value

Daily compliance >3 h (n = 24)

Daily compliance <3 h (n = 9)

p Value

67.1 ± 13.1 50/6 30.4 ± 5.4

56.2 ± 12.2** 17/1* 29.4 ± 3.4

<0.001 0.04 0.49

62.0 ± 14.3 28/4 31.0 ± 5.8

55.0 ± 13.3 9/0 27.6 ± 3.3

0.20 0.23 0.16

73.8 ± 7.0 22/2 29.6 ± 4.6

57.3 ± 11.8** 8/1 31.0 ± 2.9

<0.001 0.19 0.33

8.9 ± 5.2 52.8 ± 22 7 92.4 ± 2.0 79.0 ± 10.2 18.9 ± 20.9

9.2 ± 6.4 53.6 ± 27.8 91.2 ± 3.7 77.8 ± 11.0 25.6 ± 29.3

0.89 0.98 0.21 0.64 0.69

10.5 ± 4.7 52.0 ± 24.3 92.5 ± 2.3 79.7 ± 8.7 17.6 ± 23.4

11.6 ± 7.3 53.1 ± 24.0 92.8 ± 3.0 80.8 ± 10.9 14.2 ± 25.0

0.65 0.90 0.52 0.52 0.40

7.1 ± 5.1 54.0 ± 20.5 92.3 ± 1.5 78.1 ± 11.9 20.6 ± 17.4

5.8 ± 2.4 54.0 ± 32.6 89.6 ± 3.7 74.4 ± 10.6 37.0 ± 30.2

0.9 0.73 0.07 0.24 0.07

Hemodynamic parameters Clinical SBP (mmHg) Clinical DBP (mmHg) LVEF(%)

143 ± 21 79 ± 13 NA

132 ± 14* 81.1 ± 11.8 NA

0.01 0.65 –

141.6 ± 18.1 78.8 ± 12.0 NA

133.0 ± 10.7 78.9 ± 11.5 NA

0.28 0.90 –

145.4 ± 24.8 80.3 ± 13.7 38.8 ± 12.2

130.9 ± 16.8 83.0 ± 12.3 42.3 ± 16.3

0.12 0.61 0.97

Arterial blood gases pH PaCO2 (kPa) PaO2 (kPa) SaO2 (%) HCO3- (mmol/l)

7.43 ± 0.02 4.82 ± 0.56 10.4 ± 2.1 96 ± 2 24.4 ± 2.0

7.43 ± 0.02 4.89 ± 0.43 10.5 ± 1.7 96 ± 2 24.6 ± 2.2

0.95 0.67 0.54 0.79 0.80

7.43 ± 0.02 4.90 ± 0.55 10.1 ± 1.4 96 ± 2 24.6 ± 1.7

7.44 ± 0.03 4.85 ± 0.40 11.4 ± 1.7* 97 ± 2* 24.9 ± 2.0

0.32 0.34 0.05 0.05 0.67

7.44 ± 0.03 4.73 ± 0.57 10.83 ± 2.74 96 ± 2 24.1 ± 2.3

7.43 ± 0.02 4.92 ± 0.47 9.68 ± 1.38 95 ± 2 24.4 ± 2.4

0.33 0.38 0.14 0.3 0.75

Anthropometric data Age (years) Male/female (number) BMI (kg/m2) Sleep studies Epworth score AHI (nb/hour of recording) Mean nocturnal SaO2 (%) Minimal nocturnal SaO2 (%) Time spent under 90% of SaO2 (% of recording time)

Values are mean ± SD. BMI, body mass index; AHI, apnea + hypopnea index; SBP, systolic blood pressure; DBP, diastolic blood pressure; LVEF, left ventricular ejection fraction; NA, not available; NS, not significant. * p < 0.05 for comparison between non-CHF and CHF subgroups. ** p < 0.01 for comparison between non-CHF and CHF subgroups.

addressed by the on-going large multicenter randomized controlled trial comparing ASV to optimal medical therapy in CHF patients (SERVE HF study: more than 700 patients included to date, with a total of 1260 patients expected to be enrolled, NCT00733343). Although they exhibit poor sleep quality, CHF patients do not generally complain of sleepiness [15,29]. Indeed, ESS scores were in the normal range in our CHF patients with CSA and did not improve after ASV treatment, a finding already reported by Pepperell et al. [18] and Philippe et al. [16]. However, objective sleepiness assessed by the Osler Test significantly improved [18] with effective ASV compared to sub-therapeutic ASV and a non-significant increase in sleep latencies was found on MWT (+1.1 min) in one study [16] Additionally, in our study, CHF patients treated by ASV significantly improved NYHA, status which is compatible with improvements in quality of life reported previously [16,30]. In France, a recent survey among experienced clinicians involved in non-invasive ventilation showed that half of the prescriptions for home treatment by ASV were related to non-CHF CSA (unpublished data). However, in this field, efficacy data are clearly lacking. Allam et al. published the first report of the clinical use of ASV in a consecutive series of patients suffering from various causes of central sleep apnea, including CompSAS, stroke, opioids intake, and CSR/CSA associated with cardiac failure [21]. ASV appeared superior to CPAP and BPAP-S/T in the treatment of these causes of CSA. Our results confirm these findings in larger sub-groups of patients and further show that ASV alleviates sleep respiratory instability by reducing chronic hyperventilation. With regards to idiopathic CSA, to date, only three patients have been reported as successfully treated by ASV [20]. As expected, these three patients were unsuccessfully treated by CPAP or oxygen first but improved with ASV. Our study included the largest group of idiopathic CSA treated by ASV and we demonstrated a dramatic improvement in sleep abnormalities. The efficacy of ASV remains still debated for treating CSA in patients chronically treated by opioids. A first study reported numerous residual central events

when wearing the device [19] but ASV settings had probably not been optimized in that study [31]. In a subsequent study, using a better titration of the device, Javaheri et al. demonstrated, in five patients, that ASV can successfully support patients chronically on opioid medications who exhibit periodic breathing [32]. Opioid intake can also lead to ataxic respiration [19] with hypercapnia and blunted ventilator responses [33]. The appropriate ventilatory mode in this situation is then fixed pressure support [34] with high backup frequency rather than ASV. This was nicely shown in a case control study of 44 subjects titrated with Bilevel ST using a fixed pressure support and an unfixed back up rate. Indeed, this setting was able to resolve central apneas [35]. In our patients with CSA unrelated with CHF, Epworth sleepiness scale improved only in the sub-group of compliant patients. Thus, overall, we can conclude that ASV is probably the best ventilatory mode to correct sleep disturbances and improve subjective sleepiness in CompSAS [21], idiopathic CSA, and in neurological diseases leading to hypocapnic CSA. Further studies are needed to evaluate prognosis implication of central sleep apnea by itself and the impact of such treatment on survival and potentially associated cardiovascular consequences. 4.2. ASV compliance In CHF patients, compliance has already been demonstrated as higher with ASV than with CPAP [16,24]. We report the first data on ASV compliance rates in other etiologies of CSA. The compliance rate was high, with 78% of the patients using the device more than three hours per night. Overall, the long term device tolerance and acceptance was excellent. 4.3. Impact of ASV on the mechanisms underlying sleep respiratory instability Chronic hyperventilation is a key issue in the occurrence of hypocapnic CSA. Because of excessive responsiveness to CO2, arousals

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Fig. 1. Impact of Adaptive Servo Ventilation (ASV) treatment on respiratory sleep disturbances in central sleep apnea patients (n = 74). ⁄p < 0.05 for intragroup comparisons without and with ASV. AHI, apnea-hypopnea index per hour; CHF, chronic heart failure; TST, total sleep time.

Fig. 2. Efficacy of 6 months Adaptive Servo Ventilation (ASV) treatment on cardiac status of chronic heart failure patients (n = 33). LVEF, left ventricular ejection fraction.

from sleep cause large increases in ventilation, and drive PaCO2 below the apneic threshold, triggering central events. This repetitive cycle induces cyclic sympathetic activation. By exposing healthy human subjects to intermittent hypoxia during 14 nights, we demonstrated an increase in muscle nerve sympathetic activity associated with an increase in chemoreflex sensitivity [36]. ASV aims to correct episodes of apnea and hypopnea and subsequently reduce

arousals, sleep fragmentation, and sympathetic activation. After one month of therapeutic ASV compared to subtherapeutic ASV, significant falls occurred in urinary adrenaline excretion [18]. This is mainly explained by the suppression of oxygen desaturations, which leads to a reduction in chemoreflex sensitivity and chronic hyperventilation. A strength of our study was to have systematically assessed the evolution of blood gases on ASV. Our results

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showed a significant increase in PaCO2 and a reduction of alkalosis suggesting that long term use of ASV effectively reduced chronic hyperventilation. In cardiac failure patients, excessive daytime ventilation induces low diurnal PaCO2. This brings patients close to their apnea threshold and then promotes central apneas during sleep. Increase in nocturnal PaCO2 obtained with low levels of inspired CO2 (2– 3%), the addition of an external dead-space, or both, have been shown to stabilize ventilation and remove CSA efficiently. However, Javaheri et al. [37] showed that hypocapnia is not predictive of CSA in liver cirrhosis patients. This argues against an independent role in the low PaCO2, and promotes instead the role of DPaCO2 (i.e. prevailing PaCO2 minus apneic threshold PaCO2) as the critical factor for central sleep apnea occurrence. 4.4. Study limitations Despite the fact that our study was based on retrospective chart review, our data provide a strong rationale for prospective studies required to confirm our findings. Because of the study design, we did not always have an accurate history of medication changes throughout the follow-up period for all patients. We acknowledge that some medication modifications might have had a significant impact on ASV efficacy. 5. Conclusion Our findings clarify and extend prior observations on ASV treatment. We suggest that in a real life environment ASV is well tolerated and effective for most patients with central sleep apnea with hypocapnia and chronic hyperventilation. Author contributions Pr. Pépin had access to and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr. Carnevale contributed to study design, data analysis, and manuscript preparation. Dr. Georges contributed to data analysis and manuscript preparation. Dr. Rabec contributed to patient recruitment, data analysis, and manuscript preparation. Dr. Tamisier contributed to patient recruitment, data analysis, and manuscript preparation. Pr. Lévy contributed to patient recruitment, data analysis, and manuscript preparation. Pr. Pépin contributed to study design, data analysis, and manuscript preparation. 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: doi:10.1016/j.sleep.2011.07.008. None declared. Aknowledgments The authors aknowledge the help of Nathalie Arnol and Julie Mounier for statistical analysis. The study was supported by an unrestricted Grant from ResMed™. The sponsors had no role in data collection, analysis, or interpretation.

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