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APPENDIX
Supplementary Methods
Original CPAP Initiation
After an initial diagnostic study, all subjects participated in another overnight polysomnography
on continuous positive airway pressure (CPAP) after becoming familiar with the device. CPAP
was initiated at 4 cm H2O, and the pressure was progressively and gradually increased up to 10
cm H2O or until the highest pressure tolerated was reached. CPAP with a fixed pressure level
was determined for each subject. Then, they have started CPAP treatment and continued it for at
least 3 months.
Principles of Operation of ASV
The principle of operation of this adaptive-servo ventilation (ASV) device (HEARTPAP,
Respironics, Murrysville, Pennsylvania) has been described previously (1,2). Briefly, this ASV
provides a manually set level of expiratory positive airway pressure (EPAP) to maintain upperairway patency and automatically modulates the inspiratory positive airway pressure (IPAP)
within a preset range to maintain a target peak inspiratory airflow, thereby eliminating central
sleep apnea (CSA) events. Besides, the device provides an automatic backup rate, should
sustained apnea be detected.
Principles of Titration for CPAP or ASV
2
During the titration study in the CPAP-mode group, pressure levels were manually modulated
from the currently used levels to 12 cm H2O if necessary. Finally, an appropriate fixed pressure
was identified. The principle of titration for ASV which has been previously described was used
(2). First, the EPAP was manually titrated from 4 cm H2O to the effective pressure, with a
maximum of 10 cm H2O, using a similar titration method to that used for CPAP. The minimal
IPAP was set at the determined EPAP level or to EPAP + 2 cm H2O in patients with obstructive
flow limitation. The maximal IPAP was set to 10 cm H2O greater than IPAP min. In addition, all
subjects were initially set to an automatic back-up rate. When the central apneas were not
corrected, the automatic backup rate was changed to the fixed back-up rate of 10 breaths/min or
more. Subsequently, if continued periodic breathing was observed, maximal IPAP was raised by
2 cm H2O. Initially, all subjects in both groups were given CPAP of 2 cm H2O below the
currently used level or 4 cm H2O until sleep onset, and the CPAP of currently used levels for the
CPAP-mode group or the ASV for the ASV-mode group was provided.
All subjects were blinded to their assignment throughout the study period. After titration,
all subjects were instructed to use the ASV device at home with the assigned mode; a 15- to 25min ramp time to start optimal CPAP levels or an appropriate ASV-mode was also provided to
minimize the perception of differences between the 2 modes.
Intervention Protocol
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After baseline assessment, all enrolled subjects were provided the ASV device to use in place of
their CPAP device. Patients were then randomly assigned to one of two therapeutic modes:
CPAP-mode or ASV-mode. Patients underwent titration of the assigned mode during an
overnight polysomnography. During the titration study in the CPAP-mode group, pressure levels
were manually modulated from the currently used levels to 12 cm H2O if necessary. Finally, an
appropriate fixed pressure was identified. In the ASV-mode group, previously described
principles of titration for ASV were used (2). Briefly, EPAP was manually titrated with a
maximum of 10 cm H2O. Minimal IPAP was set at the determined EPAP level or to EPAP + 2
cm H2O in patients with obstructive flow limitation. Maximal IPAP was set to 10 cm H2O above
minimal IPAP. Back-up rate was set as an automatic or fixed rate of >10 breaths/min when the
central apneas were not corrected. If continued periodic breathing was observed, maximal IPAP
was raised by 2 cm H2O. After titration, all subjects were instructed to use the ASV device at
home with the assigned mode. All subjects were blinded to their assignment throughout the study
period.
Measurements
Overnight and in-laboratory, attended polysomnography was performed using a digital
polygraph (SomnoStar α Sleep System, SensorMedics Corp, Yorba Linda, California). Generally
accepted definitions and scoring methods for sleep stage and arousals were used (3,4).
Respiratory events were scored as previously described (5). Apnea was defined as cessation of
inspiratory airflow ≥10 s. All such events were counted regardless of desaturation degree or
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arousal. The absence of airflow in the upper airway with and without ribcage and/or abdominal
movement was defined as obstructive and central apnea, respectively. Hypopnea was defined as
a discernible reduction of airflow or thoracoabdominal movement lasting for 10 s, resulting in
arousal or at least a 3% drop in arterial oxyhemoglobin saturation. We classified hypopnea as
obstructive apnea if paradoxical thoracoabdominal movements occurred or if airflow decreased
disproportionately to the reduction in the thoracoabdominal movements. The effectiveness of
CSA treatment was evaluated at baseline and 3 months after randomization. Nightly usage was
measured by the machine’s built-in counter. Applied pressure was also recorded in the device,
and the mean value during the follow-up period was automatically calculated. The CPAP level
before study enrollment and nightly CPAP usage for 3 months before enrollment were also
determined.
At baseline and follow-up polysomnography, body mass index, sleepiness, arterial
blood gas, cardiovascular variables such as blood pressure, heart rate, plasma B-type natriuretic
peptide (BNP) by the chemiluminescent enzyme immunoassay (Architect·BNP-JP, Abbott Japan
Co. Ltd., Chiba, Japan), 24-h urinary norepinephrine excretion (UNE) by the HPLC method
(HLC-725CAII, Tosoh Co. Ltd., Tokyo, Japan), distance walked in 6 min (6MWD), LVEF, left
ventricular end-diastolic and end-systolic diameters (LVEDD and LVESD, respectively), mitral
regurgitation (MR) area, and quality of life (QOL) were assessed. Sleepiness was subjectively
evaluated using the Epworth sleepiness scale (6). An arterial blood sample was collected while
patients were awake after 30-min rest periods while in the supine position. Blood samples for
BNP measurement were obtained in the early morning. Urine was collected for a 24-h period
from arrival at hospital to the next day just after polysomnography. Data were presented as 24-h
UNE adjusted by creatinine excretion. The protocol for the 6-min walk test has been described
5
(7). The total 6MWD was measured and assessed. Two-dimensional echocardiographic images
were obtained from the parasternal long- and short-axes, apical long-axis, and apical fourchamber views. LVEDD and LVESD were determined, and LVEF was calculated according to
the modified Simpson’s method. Averaged values of five consecutive beats were used. As a MR
area, ratio of the area of color-flow Doppler regurgitant jet per the area of the left atrium in
systole as percentages were calculated. The sonographers were blinded to treatment mode
assignments and were not involved in the present study. QOL was assessed using the short-form
36 questionnaire (8).
Statistical Analysis
All values are shown as the mean ± SD for normally distributed data and as the median
(interquartile range) for non-normally distributed data. Categorical variables are expressed as
numbers and percentages. Patient characteristics at baseline were compared using the Student t
test for normally distributed data, the Mann-Whitney U test for non-normally distributed data for
continuous variables, and the chi-square test or Fisher exact test for categorical variables. Twoway repeated measures analysis of variance, followed by the Tukey test, was used to compare
within- and between-group differences in variables measured at baseline and 3 months later. For
non-normally distributed data, natural log-transformed values were used for analyses. A p value
<0.05 was considered statistically significant. All statistical analyses were performed using SAS
version 9.1 (SAS Institute Inc., Cary, North Carolina).
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Supplementary References
1.
Kasai T, Narui K, Dohi T, et al. First experience of using new adaptive servo-ventilation
device for Cheyne-Stokes respiration with central sleep apnea among Japanese patients
with congestive heart failure: report of 4 clinical cases. Circ J 2006;70:1148–54.
2.
Kasai T, Usui Y, Yoshioka T, et al. Effect of flow-triggered adaptive servo-ventilation
compared with continuous positive airway pressure in patients with chronic heart failure
with coexisting obstructive sleep apnea and Cheyne-Stokes respiration. Circ Heart Fail
2010;3:140–8.
3.
Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and
scoring for sleep stages of human subjects. Los Angele, Calif: UCLA Brain Information
Service/Brain Research Institute, 1968.
4.
EEG arousals: scoring rules and examples: a preliminary report from the Sleep Disorders
Atlas Task Force of the American Sleep Disorders Association. Sleep 1992;15:173–84.
5.
Dohi T, Kasai T, Narui K, et al. Bi-level positive airway pressure ventilation for treating
heart failure with central sleep apnea that is unresponsive to continuous positive airway
pressure. Circ J 2008;72:1100–5.
6.
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness
scale. Sleep 1991;14:540–5.
7.
Guyatt GH, Sullivan MJ, Thompson PJ et al. The 6-minute walk: a new measure of
exercise capacity in patients with chronic heart failure. Can Med Assoc J 1985;132:919–
23.
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8.
Jenkinson C, Stradling J, Petersen S. Comparison of three measures of quality of life
outcome in the evaluation of continuous positive airways pressure therapy for sleep
apnoea. J Sleep Res 1997;6:199–204.
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Online Figure 1 Effects of ASV and CPAP Modes on QOL
Of the 8 subscales of the 36-Item Short Form Health Survey (SF-36), changes in PF, BP, GH,
VT, and MH were significantly different, whereas changes in RP, SF, and RE were not
significantly different between the two groups. Changes in GH and VT were significantly
different within groups. *p < 0.05 between groups; †p < 0.01 between groups; ‡p < 0.05 vs.
baseline; §p < 0.01 vs. baseline. BP = bodily pain; GH = general health perception; MH = mental
health; PF = physical functioning; RE = role limitations due to emotional problems; RP = role
limitations due to physical problems; SF = social functioning; VT = vitality.