Sleep Breath (2016) 20:635–646
DOI 10.1007/s11325-015-1265-0
SLEEP BREATHING PHYSIOLOGY AND DISORDERS • ORIGINAL ARTICLE
Comparison of effects of OSA treatment by MAD and by CPAP
on cardiac autonomic function during daytime
Martin Glos 1 & Thomas Penzel 1 & Christoph Schoebel 1 & Georg-Reiner Nitzsche 1 &
Sandra Zimmermann 1 & Christopher Rudolph 1 & Alexander Blau 1 & Gert Baumann 2 &
Paul-Georg Jost-Brinkmann 3 & Stefanie Rautengarten 4 & Jan Christian Meier 3 &
Ingrid Peroz 4 & Ingo Fietze 1
Received: 7 January 2015 / Revised: 7 September 2015 / Accepted: 21 September 2015 / Published online: 13 October 2015
# The Author(s) 2015. This article is published with open access at Springerlink.com
Abstract
Purpose The present study compared the effects of mandibular advancement therapy (MAD) with continuous positive airway pressure therapy (CPAP) on daytime cardiac autonomic
modulation in a wide range of obstructive sleep apnea (OSA)
patients under controlled conditions in a randomized, twoperiod crossover trial.
Methods Forty OSA patients underwent treatment with MAD
and with CPAP for 12 weeks each. At baseline and after each
treatment period, patients were assessed by polysomnography
as well as by a daytime cardiac autonomic function test that
measured heart rate variability (HRV), continuous blood pressure (BP), and baroreceptor sensitivity (BRS) under conditions of spontaneous breathing, with breathing at 6, 12, and
15/min.
Results Both CPAP and MAD therapy substantially eliminated apneas and hypopneas. CPAP had a greater effect. During
daytime with all four conditions of controlled breathing, threeminute mean values of continuous diastolic BP were significantly reduced for both MAD and CPAP therapy. At the same
time, selective increases due to therapy with MAD were found
* Martin Glos
martin.glos@charite.de
1
Center for Sleep Medicine, Charité—Universitätsmedizin Berlin,
CCM-CC11, Charitéplatz 1, 10117 Berlin, Germany
2
Department of Cardiology and Angiology,
Charité—Universitätsmedizin Berlin, CCM-CC11, Berlin, Germany
3
Department of Dentofacial Orthopedics, Orthodontics, and
Pedodontics, Charité—Universitätsmedizin Berlin, CBF-CC3,
Berlin, Germany
4
Department of Prosthodontics, Geriatric Dentistry and
Craniomandibular Disorders, Charité—Universitätsmedizin Berlin,
CBF-CC3, Berlin, Germany
for HRV high frequency (HF) values. No changes were observed for BRS in either therapy mode.
Conclusions These findings indicate that both MAD and
CPAP result in similar beneficial changes in cardiac autonomic function during daytime, especially in blood pressure.
CPAP is more effective than MAD in eliminating respiratory
events.
Keywords Mandibular advancement device . Obstructive
sleep apnea . Cardiac autonomic function . Blood pressure .
Continuous positive airway pressure . Heart rate variability .
Baroreceptor sensitivity
Introduction
Obstructive sleep apnea (OSA) is the most common form of
sleep-disordered breathing and affects about 5–7 % of the
adult population [1]. Repetitive collapses of the upper airways
during sleep lead to hypoxic phases with associated sleep
fragmentation and sympathetic activation, the latter of which
also persists during daytime with the resultant consequences
[2]. OSA has accordingly been confirmed as an independent
cardiovascular risk factor that may increase mortality if left
untreated [3]. Continuous positive airway pressure (CPAP)
therapy is manifestly an effective therapeutic approach. Many
studies have demonstrated that CPAP therapy reduces cardiovascular risk and overall mortality rate if regularly employed
by OSA patients [2–4]. CPAP therapy is accordingly recommended as the standard therapy in moderate to severe OSA.
The CPAP effect can partly be explained by its reduction of
sympathetic tone not only during the night but also during
daytime [5].
In addition to investigation of blood pressure [4] and heart
rate variability (HRV) [6], measurements of baroreceptor
636
sensitivity (BRS) and of systolic blood pressure variability
(SBPV) represent non-invasive methods of assessing autonomic activity [7]. Regular CPAP therapy improves these parameters during the night and daytime as evidence of reduction of sympathetic hyperactivation in OSA patients [5, 8].
Many trials have dealt with the effect of CPAP on HRV [9],
and others have likewise reported the positive effect of CPAP
on BRS [9, 10].
Unfortunately, many patients demonstrate limited adherence to CPAP therapy, and some patients decline this form
of treatment. There is accordingly a need for alternative therapeutic approaches that are as effective as CPAP therapy—not
only with respect to symptoms but also to the cardiovascular
consequences of OSA.
Intraoral mandibular advancement devices (MAD) protrude the mandible during sleep to maintain upper airway
patency [11]. A number of trials have shown comparable effects of MAD and CPAP in OSA patients with regard to
symptoms such as daytime sleepiness and driving performance—but have also covered side effects, withdrawal rates,
and usage time [12, 13]. Although MAD evidently does not
reduce apnea-hypopnea index (AHI) by the same amount as
CPAP [12–14], more favorable side effects, withdrawal rates,
and usage time may be explained by better compliance and
quality of life in patients who employ MAD compared with
those who use CPAP [13]. This was also confirmed by other
randomized controlled trials that investigated the effects of
both therapies [15–21]. MAD has thus been proposed as alternative therapeutic approach for mild to moderate OSA, in
accordance with existing guidelines [2, 22]. Some investigators have demonstrated subjective benefits of MAD for patients classified with severe OSA [13, 18, 23]. Studies of
MAD therapy, however, are often not comparable. Furthermore, the few studies that until now have examined the effects
of MAD therapy on cardiovascular parameters have arrived at
contradictory findings. Gotsopoulus et al. [24] found a small
reduction in diastolic blood pressure during daytime, whereas
Andren et al. [25] reported improvement in systolic blood
pressure. Phillips et al. [13] showed that regular use of neither
CPAP nor MAD for 1 month can improve 24-h ambulatory
mean blood pressure, whereas they are comparably effective
with respect to daytime sleepiness and quality of life.
Little is known about the effect of MAD therapy on
autonomic activity parameters. One study investigating
daytime HRV parameters [26] found that 3 months of
MAD therapy improved cardiac autonomic modulation.
Dal-Fabbro et al. [27] investigated effects of 1-month
MAD and CPAP therapy on HRV during sleep and
found a number of beneficial changes for both
therapies.
To date, none of the previous studies has specifically explored in parallel the effect of MAD on daytime blood pressure, HRV, BRS, and SBPV. There are likewise no systematic
Sleep Breath (2016) 20:635–646
comparisons between MAD and CPAP for these parameters in
the same patients.
The present study therefore aimed to evaluate the effect of
MAD and CPAP with regard to cardiovascular parameters and
autonomic activity in a two-period crossover design in which
the patients were either randomized to the sequence MAD–
CPAP (12 weeks of MAD followed by 12 weeks of CPAP) or
the sequence CPAP–MAD (3 months of CPAP followed by
3 months of MAD).
Subjects and methods
Participants
Eighty-four patients with suspicion of OSA syndrome were
asked to participate in the study. The study was approved by
the local ethics committee of the university hospital Charité—
Universitätsmedizin Berlin, and participants gave their written
consent for participation.
Inclusion criteria were an AHI of ≥5/h and an age of
≥18 years. Patients with severe OSA (AHI >30/h) requiring
treatment were included only if they did not demonstrate clear
indication for CPAP such as a severe cardiovascular risk, e.g.,
myocardial infarction, stroke, atrial fibrillation, resistant hypertension, or heart failure. An essential element for inclusion
of any patient was a clinical symptom complex, as well as
suffering owing to lack of refreshing sleep.
Exclusion criteria were drug abuses, any medication intake
that could influence sleep, any presence of sleep disorders
other than OSA, any kind of specific medication for OSA in
the patient’s case history, prior use of any form of PAP therapy, any prior pharyngeal surgery (UPPP, LAUP, or RFT) for
OSA therapy, any psychiatric or neurological diseases previously known or arising during the study that could impair
compliance, atrial fibrillation, any medication that could affect
heart rate, craniomandibular disorders with restricted mobility
of the lower jaw (especially restrictions to protrusion), acute to
subacute dental treatment requirements (e.g., caries treatment), >8 stable natural teeth per jaw (with maximum average
Periotest value per tooth <20), acute periodontal disease, class
III dental relationship with anterior crossbite, participants in
orthodontic retention for less than 6 months, and discontinuation of therapy or interruption of therapy for more than
1 week.
Participants who had taken part in a clinical pharmacological trial up to 4 weeks before entering the study were also
excluded.
Study procedure
Patients with reported symptoms of OSA were asked to participate in the study. After receiving written consent for
Sleep Breath (2016) 20:635–646
637
participation in the study, they received a 6-channel ambulatory sleep apnea monitoring device (Embletta pds, Embla Inc.,
Broomfield, CO, USA), which included recording airflow,
snoring, thoracic and abdominal efforts, oxygen saturation,
leg movements, and body position. In addition to a physical
examination, a general medical case history, and a specific
sleep disorder case history, patients were asked to complete
the form on the Epworth Sleepiness Scale (ESS) as well as the
Insomnia Severity Index (ISI). A dental examination and
screening for craniomandibular disorders (CMD) were performed by a dentist.
If patients were eligible by the applied inclusion/exclusion
criteria, they were randomized in a crossover fashion to either a)
receiving MAD (SomnoDent®, Somnomed Europe AG, Zurich,
Switzerland) as initial therapy for 12 weeks followed by CPAP
(REMstar Pro, Philips Respironics, Murrysville, PA, USA)
therapy for another 12 weeks (sequence group MAD–CPAP)
or b) receiving CPAP as initial therapy for 12 weeks followed
by a MAD therapy for another 12 weeks (sequence group
CPAP–MAD). The entire study protocol is illustrated in Fig. 1.
If patients had been randomized to initially receive MAD
therapy, the MAD was individually produced and fitted to the
patient 1–2 weeks prior to the beginning of the therapy (T1)
by the manufacturer (Somnomed Europe AG, Zurich, Switzerland) and by a dentist. At T1 in both treatment arms, patients were investigated by polysomnography (PSG) for three
consecutive nights without gap. The first night served as baseline PSG, and the subsequent two nights were titration nights
to the initial therapy upon randomization. Criteria for the remaining in the study were an AHI of at least 5/h and exclusion
of a relevant PLMD syndrome (PLMI <10/h) or other relevant
movement disorders during baseline PSG.
After baseline PSG on the following day, patients were
investigated by a cardiac autonomic function test.
For patients who had been randomized to receive the MAD,
titration with the MAD took place during the first of the two
titration nights with an individually adjusted protrusion of up to
70 % of the possible maximum. If the AHI remained ≥10/h after
the first titration night, the protrusion was individually increased,
as recorded by a gauge by another 10 % of the patient’s maximum protrusion capacity during the second titration night.
For patients who had been randomized to receive CPAP
therapy during the two titration nights, manual titration was
performed to eliminate apneas, hypopneas, oxygen
desaturations, and respiratory arousals.
After the three baseline PSG nights at T1, the patients were
sent home for 12 weeks of continuous use of therapy during
sleep with either MAD or CPAP. Afterward, the patients were
invited to the sleep lab for another 3 consecutive nights without gap by PSG (T2).
For patients who had been randomized to receive the MAD
as the following therapy, the MAD was individually produced
and fitted to the patient by a dentist 1–2 weeks prior to the
beginning of this therapy (T2).
During the first PSG at T2, patients were investigated while
using the therapy that they had initially applied to measure the
12-week therapeutic effect on sleep.
After PSG on the following day, patients were again investigated by a cardiac autonomic function test to measure the 12week therapeutic effect of the initial therapy on daytime cardiovascular functions.
The subsequent two PSGs of T2 served as titration nights
for the following therapy mode and were performed as described for T1. After the three subsequent PSG nights at T2,
patients were sent home for 12 weeks of continuous use of the
following therapy. After this period, patients were invited to
the sleep lab for a single night with PSG (T3). Patients were
investigated by PSG to measure the therapeutic effect on sleep
PSG (1night)
n=24 MAD device
fitting
Baseline
T3
T2
T1
Cardiac autonomic
function test
PSG (2 nights)
Baseline
Titration for MAD
PSG (1night)
Cardiac autonomic
function test
PSG (2 nights)
MAD
MAD
Titration for CPAP
n=24
- ambulatory sleep
apnea monitoring
- anamnesis
- questionnaires
- dental function
- randomization
PSG (1night)
Cardiac autonomic
function test
CPAP
CPAP
CPAP therapy
(12 weeks)
MAD therapy
(12 weeks)
n=84
n=21
Dropouts:
- personal reasons (n=2)
- technical failure (n=1)
n=48
PSG (1night)
n=24
Baseline
Cardiac autonomic
function test
PSG (2 nights)
Baseline
Titration for CPAP
n=24
PSG (1night)
Cardiac autonomic
function test
PSG (2 nights)
CPAP
CPAP
Titration for MAD
MAD device
fitting
CPAP therapy
(12 weeks)
n=40
n=19
PSG (1night)
Cardiac autonomic
function test
MAD
MAD
MAD therapy
(12 weeks)
Dropouts:
- insufficient compliance (n=2)
- intolerance to CPAP (n=3)
Fig. 1 Flow diagram of the study: T1 at the beginning of therapy, T2 after 12 weeks of initial therapy, and T3 after another 12 weeks with the following
therapy
638
by the therapy that they had employed during the previous
12 weeks. After PSG on the following day, patients were
investigated once again by a cardiac autonomic function test
to measure the 12-week therapeutic effect on daytime cardiovascular functions.
Polysomnography
PSG was performed in a sleep lab certified by the German
Sleep Society Board according to the American Academy of
Sleep Medicine (AASM) guidelines by using an Embla
N7000 recorder (Embla systems, Broomfield, CO, USA).
Manual scoring of sleep resulted in the following parameters: percentage of sleep stages N1, N2, N3, and R of total
sleep time (% TST); sleep latency (SL); wake time after sleep
onset (WASO); and sleep efficiency (SE). Manual scoring of
respiratory events during sleep enabled calculation of the apnea index (AI), the hypopnea index (HI), the AHI, and the
oxygen desaturation index (ODI).
Scoring of sleep and respiratory events took place according to the AASM guidelines.
Cardiac autonomic function test
The cardiac autonomic function test was performed in the
morning hours during wakefulness in a quiet room of the sleep
lab. Patients were instructed not to use caffeine or vasoactive
drugs during the morning of the test. Patients were studied in a
45° head-up position and were trained in metronomically controlled breathing at varying respiration frequencies, for a duration of 5 min in each case. Non-invasive continuous blood
pressure was recorded with the Portapres® system (Finapres
Medical Systems, Amsterdam, The Netherlands). This method correlates well with intra-arterial blood pressure values and
proved to be valid for time- and frequency-domain analysis of
blood pressure variability and BRS [28]. In parallel, ECG
(lead II), respiration with a thoracic effort belt, and nasal airflow were recorded using a PSG recorder (Embla systems,
Broomfield, CO, USA). Subjects were instructed to breathe
a) spontaneously, b) at a fixed rate of 6/min, c) at a fixed rate of
12/min, and d) with a fixed rate of 15/min. This protocol had
likewise been used in earlier studies [29–31]. The fixed
breathing rates were presented to the patients by a metronome.
The sequence of these episodes of forced breathing, uniformly
specified for every patient, included breaks of 2 min in which
Riva-Rocci office blood pressure measurements were taken
before raising the breathing rate.
The sampling rate was set to 200 Hz for the ECG and the
continuous finger blood pressure signals and to 50 Hz for the
respiration signals. The recording time duration for the four
subsequent breathing modalities was 5 min each.
Sleep Breath (2016) 20:635–646
Continuous heart rate and blood pressure analysis
The ECG and the continuous blood pressure signals recorded
with the cardiac autonomic function test were analyzed using
the MATLAB® software (The Math-Works Inc., Natick, MA,
USA), with algorithms as previously described [29, 32]. After
offline filtering of 5-min signals using a Butterworth band
pass (0.3–70 Hz) for each subsequent heartbeat, measurement
of the following took place by peak-detection algorithms: the
RR interval, the systolic blood pressure, and the diastolic
blood pressure. Beat-to-beat mean blood pressure values were
obtained by integration of continuous blood pressure values
between subsequent heartbeats. Artifacts were thereafter removed and episodes of 3 min in which the breathing pattern
was stable were selected for further analysis from the 5 min
records. Interpolation of the time series then followed at 4 Hz
by using a cubic spline interpolation algorithm.
In the time domain, we calculated the mean heart rate, the
standard deviation of NN intervals (SDNN), and the root
mean square of successive differences (RMSSD). In the frequency domain, fast Fourier transformation was applied to
calculate power spectra of HRV and SBPV. For each of the
two spectra, the low frequency (LF 0.04 to 0.15 Hz) and high
frequency (HF 0.15 to 0.4 Hz) spectral bands were calculated.
For subjects in the supine position under controlled respiration without pharmacological or physical interventions, it
can be assumed that the HRV HF band is primarily modulated
by vagal activity, whereas the LF band reflects both sympathetic and vagal autonomic activity [33]. The LF/HF-HRV
ratio was calculated as a surrogate for sympathovagal balance.
An increase in the LF/HF-HRV ratio indicates a shift toward a
sympathetic predominance in which higher sympathetic activity is causative as long as the HF component remains unchanged. SBPV components in the LF range are related to
sympathetic activity, although this relationship is not specific.
HF-SBPV component modulations are due to mechanical effects of respiration.
BRS is based on the permanent activity of the baroreflex
feedback loop, in which amplitude fluctuations of blood pressure are transferred to corresponding heart rate changes. By
use of spectral analysis of spontaneous heart and systolic
blood pressure changes, it was possible to calculate spontaneous BRS by applying the square root of the ratio of RR interval and systolic blood pressure (SBP) power spectra. BRS
values are expressed in milliseconds per millimeter of mercury
(msec/mmHg).
This calculation was performed individually for the LF
(0.04 to 0.15 Hz) and HF (0.15 to 0.4 Hz) spectral bands,
which produced α-LF and α-HF [34] results. The squared
coherence function (k2) was used to evaluate the statistical
reliability of α-LF and α-HF. Data were further utilized if k2
exceeded 0.56 [35]. Under normal breathing conditions, α-LF
shows the gain in the ratio of arterial pressure to RR interval in
Sleep Breath (2016) 20:635–646
the spectral region not linked to breathing frequency. The αHF component reflects the gain in the spectral region of the
breathing frequency [34]. As a final point, α-tot was calculated as the mean of α-LF and α-HF and serves for evaluation of
the overall baroreceptor gain [34].
Statistics
For all statistical analysis, we set the alpha level at p<0.05 and
employed the IBM software SPSS® Statistics, version 20.0
(IBM Corp., Armonk, NY, USA). Values are presented as
mean±standard deviation (SD). Data presented in figures indicate values for the 5th, 25th, 50th (median), 75th, and 95th
percentiles.
To test for possible carryover effects of the therapy modes,
the Mann–Whitney test was employed between sum values of
sequence groups MAD–CPAP and CPAP–MAD.
To test for differences between measured values for baseline, 12 weeks of MAD therapy, and 12 weeks of CPAP therapy for parameters involving sleep, respiration, and the cardiac autonomic function test, the Friedman test was employed.
Post-hoc analysis to identify significant pairs was performed
by applying the Wilcoxon test.
To test for differences between MAD and CPAP treatment
modalities, the Mann–Whitney test was used for difference
values of the sequence groups MAD–CPAP and CPAP–
MAD.
639
insomnia, with an ISI score 15 to 21, was observed in another
n=7 patients.
Therapeutic effects of MAD and CPAP on PSG measures
No significant carryover effects on sleep structure or respiration were disclosed by PSG for sequence groups MAD–CPAP
and CPAP–MAD.
Sleep structure
After 12 weeks of therapy, NREM sleep stage N1 was reduced
by 7.7 %-TST for MAD (p<0.01) and by 11.6 %-TST for CPAP
(p<0.01). Comparison of treatment modalities disclosed that the
reduction was more pronounced after CPAP use than after MAD
(p<0.001). Rapid eye movement (REM) sleep increased by
2.3 %-TST for MAD (p<0.01) and by 3.9 %-TST for CPAP
(p<0.01) in reference to baseline PSG values. Slow wave sleep
(SWS) stage N3 likewise increased by 3.9 %-TST (p<0.01) after
12 weeks of CPAP therapy, whereas for MAD, no significant
changes were found. Comparison of CPAP and MAD results
revealed no differences between treatment modalities with respect to sleep stages REM and N3. Parameters N2, WASO,
SL, and SE remained unchanged with therapy in both treatment
modalities. Also, comparison of CPAP and MAD results revealed no differences between treatment modalities for these
parameters (Table 1).
Respiratory parameters
Results
Subject characteristics
Out of n=84 patients with suspicion of OSA who were initially
invited to participate, n=48 were included in the study on the
basis of inclusion and exclusion criteria. Reasons for exclusion
were periodontitis (n=20), phobia of dental work (n=3), an
AHI of <5/h (n=5), the occurrence of a central sleep apnea
syndrome (n=1), and personal reasons (n=7). After a period
of 2×12 weeks, n=40 patients (m=33, w=7) successfully completed the study. Causes for discontinuation of the study were
insufficient compliance with CPAP therapy (n=2), personal
reasons (n=2), intolerance of CPAP therapy (n=3), and data
loss due to technical failure (n=1). Mean age was 49.5±
11.8 years and BMI was 28.3±4.7 kg/m2. Mild sleep apnea
(AHI 5 to 15/h) was determined in n=3 patients, moderate sleep
apnea (AHI >15 to 30/h) in n=24, and severe sleep apnea (AHI
>30/h) in n=13. Mean ESS score was 9.2±3.9, and a value of
ESS ≥10—indicating an increased tendency to fall asleep—was
established among half the patients. The average ISI score was
10.8±4.9. Complaints of mild insomnia, expressed by an ISI
score of 8 to 14, was seen in n=22 patients, and moderate
Twelve weeks of treatment with MAD and with CPAP led
with both modalities to changes in respiratory parameters.
Mean oxygen saturation values of 94.7±1.5 % (range of
90.0 to 97.9 %) at baseline did not change after 12 weeks of
Table 1 Effect of CPAP and MAD therapy on parameters of sleep
structure from polysomnography (PSG)
Parameter
Baseline, n=40
MAD, n=40
CPAP, n=40
N1 [% TST]
N2 [% TST]
N3 [% TST]
REM [% TST]
WASO [min]
TST [min]
21.0±13.0
44.7±10.2
18.9±10.0
15.9±5.6
51.0±34.9
400.3±51.4
13.3±7.5*
47.2±11.4
21.3±11.0
18.2±5.2*
44.2±39.2
394.5±59.4
9.4±4.2*,**
46.7±13.8
22.8±11.7*
19.9±5.0*
58.5±46.9
400.5±59.1
86.9±7.9
15.9±12.4
88.2±9.4
19.4±19.7
SE [%]
SL [min]
85.8±11.6
20.2±19.8
Values are means±SD
CPAP continuous positive airway pressure therapy, MAD mandibular
advancement therapy, REM rapid eye movement, WASO wake after sleep
onset time, SE sleep efficiency, SL sleep latency
*p< 0.01 for comparison MAD vs. baseline or CPAP vs. baseline;
**p<0.001 for comparison CPAP vs. MAD
640
Sleep Breath (2016) 20:635–646
MAD therapy (94.8±1.2 %, range of 90.0 to 97.9 %), but after
CPAP therapy (95.9±1.1 %, range of 93.8 to 98.0 %) a reduction of 1.2 % (p<0.001) became apparent. Comparison of
CPAP with MAD disclosed significant difference between
treatment modalities (p < 0.001). The ODI changed from
21.5±14.8/h (range of 0.6 to 67.1/h) at baseline to 11.8±
11.4/h (range of 0.7 to 59.4/h) for MAD therapy (p<0.001)
and to 4.0±6.5/h (range of 0.0 to 29.7/h) for CPAP therapy
(p<0.001). Comparison of CPAP to MAD revealed a significant difference between treatment modalities (p<0.001).
The mean baseline AHI of 28.5±16.5/h (range of 10.8 to
83.6/h) diminished with MAD treatment by 14.8/h (p<0.001)
to 13.7±12.0/h (range of 1.3 … 59.6/h), whereas with CPAP
treatment, a reduction by 25.0/h (p<0.001) to 3.5± 5.2/h
(range 0.0 … 23.6/h) became evident (Fig. 2). Separate analysis of apneas and hypopneas revealed for the AI a reduction
from 17.8±16.5/h (range of 0.3 … 23.6/h) at baseline to 6.8±
10.3/h (range of 0.0 … 55.1/h) for MAD therapy (p<0.001)
and to 1.1±1.7/h (range of 0.0 … 8.2/h) for CPAP therapy
(p<0.001), whereas for the HI, a reduction from 11.1±7.0/h
(range of 0.0 … 37.6/h) at baseline to 7.0±6.7/h (range of 0.7
… 34.4/h) for MAD therapy (p<0.01) and to 2.4±3.8/h (range
of 0.0 … 16.2/h) for CPAP therapy (p<0.001) was present.
When comparing CPAP to MAD, there was a significant difference between treatment modalities for the AHI (p<0.001),
the AI (p<0.001), and for the HI (p<0.001). For treatment
with MAD in n=8 patients (20.0 %) and for CPAP in 33
patients (82.5 %), reduction in the number of breathing cessations to an AHI ≤5/h was observed. With assumption of a
Fig. 2 Effect of MAD and CPAP
therapy on the apnea-hypopnea
index (AHI) as determined by
polysomnography (PSG)
cutoff value of AHI ≤10/h for AHI reduction, for MAD therapy, a response thereto was established in n=22 patients
(55.0 %) and for CPAP therapy, in n=37 patients (92.5 %).
Therapeutic effects of MAD and CPAP on daytime
cardiac autonomic function
Analysis of results from the cardiac autonomic modulation
test performed during daytime with the various forced breathing patterns—i.e., a) spontaneously, b) with a fixed rate of
6/min, c) with a fixed rate of 12/min, and d) with a fixed rate
of 15/min—revealed no significant carryover effects between
sequence groups MAD–CPAP and CPAP–MAD.
Office blood pressure
Office systolic as well as diastolic blood pressure values measured by the Riva-Rocci method according to ESC/ESH
guidelines before each of the four forced breathing sequences
showed no differences after 12 weeks of MAD and CPAP
therapy. Comparison of CPAP and MAD results revealed no
differences between treatment modalities with respect to office blood pressure (Table 2).
Time domain values: RR interval, SDNN, RMSSD, and blood
pressure
In comparison with baseline, RR interval values as well as
SDNN values did not differ with either MAD therapy or CPAP
60
*
*
50
**
AHI [ /h ]
40
30
20
10
0
Baseline
MAD
*p<0.0001 for comparison MAD vs. Baseline or CPAP vs. Baseline
**p<0.0001 for comparison CPAP vs. MAD
CPAP
77.8±9.0
79.3±8.8
118.6±11.1
CPAP
MAD
79.9±16.0
78.5±8.3
122.9±15.6 117.8±13.2
Baseline
Baseline
MAD
79.7±8.5
80.7±9.8
80.3±9.0
118.3±11.2 123.8±16.0 121.1±13.6
CPAP
15/min
80.1±8.4
119.3±10.37
CPAP
6.7±3.8
9.1±8.0
7.9±5.3
0.48±0.46
0.23±0.21
3.0±4.7
0.48±0.47
0.22±0.20
4.6±6.8
7.1±4.0
9.3±6.8
8.2±5.1
32.4±59.7
22.3±30.3
2.7±4.4
26.6±29.5
15.9±22.7
2.5±3.1
6.4±2.8
9.1±7.0
7.8±4.5
0.59±0.46
0.16±0.11
7.2±10.5
37.4±61.8
19.0±31.5
3.3±3.5
11.4±5.0
15.2±10.9
13.3±7.6
0.80±0.58
0.06±0.04
15.9±11.0
11.3±5.7
13.9±9.8
12.6±7.4
0.92±0.67
0.07±0.04
18.1±12.5
10.4±5.1
14.5±11.3
12.4±8.0
7.9±3.2
10.7±6.4
9.3±4.1
1.12±0.59 * 0.35±0.19
0.09±0.09
0.17±0.11
20.7±11.9 ** 2.7±1.9
131.7±133.7 134.1±126.9 157.0±171.3 22.6±19.3
26.1±66.3 18.0±22.5
28.6±61.3
24.0±31.0
13.2±13.3 14.1±10.0
13.6±11.5
1.8±1.4
7.9±4.0
12.0±8.3
9.9±6.0
0.40±0.43
0.19±0.12
2.4±1.8
7.3±4.3
11.1±9.1
9.2±6.3
0.36±0.23
0.18±0.13
3.2±2.6
28.8±43.0
21.6±19.6
33.6±37.9 * 25.5±40.3
1.8±2.4
1.8±1.8
7.5±3.1
13.6±12.4
10.6±7.26
0.41±0.30
0.16±0.15
4.0±2.9
22.1±23.1
16.5±16.0
1.0±1.1
8.5±6.6
12.0±8.7
10.2±7.3
0.49±0.48
0.15±0.10
4.0±3.3
*p<0.05 for comparison CPAP vs. baseline or MAD vs. baseline; **trend (p<0.1) for comparison CPAP vs. baseline or MAD vs. baseline
8.4±5.0
11.7±7.2
10.0±5.8
0.39±0.38
0.15±0.11
5.0±6.8
38.9±55.6
27.8±31.0
23.4±25.3 ** 20.5±31.8
1.9±1.9
2.3±2.1
123.9±20.3 119.2±26.9 125.9±20.7 123.9±21.1 118.6±21.7 119.6±19.7 125.0±22.5 121.6±20.0 129.1±25.4 133.6±29.0 125.5±16.5 124.8±24.0
87.3±12.7 79.5±17.4 ** 81.0±11.7 ** 86.2±14.5 79.5±15.5 ** 77.8±12.6 * 86.5±13.2 81.4±13.6 ** 84.6±16.7 92.3±21.9 82.6±9.20 ** 82.9±17.8 **
69.3±13.3 60.5±17.7 * 60.9±12.1 * 68.8±14.1 61.6±15.6 * 59.4±11.8 * 69.1±12.2 62.6±13.2 ** 65.4±15.4 73.9±19.9 63.7±9.38 ** 64.2±16.5 **
934.3±128.1 942.3±98.3
35.1±18.1 36.1±20.9
26.2±20.7 26.4±17.2
79.9±9.5
122.5±14.8 117.0±12.8
MAD
12/min
931.7±123.5 952.4±123.2 958.4±131.7 973.8±164.1 940.8±131.3 960.2±107.2 948.2±114.9 949.3±126.9 957.3±107.5 962.0±106.7
41.1±19.7
56.2±31.5 57.3±30.5
60.8±33.7
39.2±15.0 39.6±21.4
39.9±21.4 37.0±15.9 45.7±26.1
45.3±22.3
27.3±19.1
39.3±37.8 36.5±23.7
41.9±40.5
26.2±15.4 30.4±18.0 ** 23.7±19.8 26.5±14.2 34.0±22.2 ** 30.2±21.3
79.6±7.4
78.6±9.3
77.8±8.8
119.6±10.5
121.9±14.1 119.6±12.6
Baseline
CPAP
Baseline
MAD
6/min
Spontaneous
CPAP continuous positive airway pressure therapy, MAD mandibular advancement therapy, SDNN standard deviation of NN intervals, RMSSD root mean square of successive differences
Values are means±SD
α-LF (ms/mmHg)
α-HF (ms/mmHg)
α-tot (ms/mmHg)
BP-syst (mmHg)
BP-mean (mmHg)
BP-diast (mmHg)
HRV
LF (ms2)
HF (ms2)
LF/HF ratio
SBPV
LF (mmHg2)
HF (mmHg2)
LF/HF ratio
BRS
Office blood pressure
Riva Rocci-syst
(mmHg)
Riva Rocci-diast
(mmHg)
Time domain
RR interval (ms)
SDNN (ms)
RMSSD (ms)
Breathing pattern
Table 2 Effect of MAD and CPAP therapy on office blood pressure and on 3 min mean values of the daytime cardiac autonomic function test under conditions of spontaneous breathing, breathing at 6,
12, and 15/min
Sleep Breath (2016) 20:635–646
641
642
Sleep Breath (2016) 20:635–646
Spontaneous
*
6/min
*
110
100
100
90
90
BP-diast [mmHg]
BP-diast [mmHg]
110
80
70
60
70
60
50
40
40
30
30
MAD
CPAP
Baseline
MAD
12/min
100
90
90
BP-diast [mmHg]
BP-diast [mmHg]
**
110
100
80
70
60
70
60
50
40
40
30
30
MAD
CPAP
**
80
50
Baseline
CPAP
15/min
**
110
*
80
50
Baseline
*
Baseline
MAD
CPAP
*p<0.05 for comparison MAD vs. Baseline or CPAP vs. Baseline
**p<0.01 for comparison MAD vs. Baseline or CPAP vs. Baseline
Fig. 3 Effect of MAD and CPAP therapy on three-minute mean values of continuous diastolic blood pressure recordings (BP-diast) under conditions of
spontaneous breathing, breathing at 6/min, 12/min, and 15/min, from the daytime cardiac autonomic function test
therapy. Again, comparison of CPAP with MAD results
disclosed no differences between treatment modalities. These
results were consistently found for all four applied respiratory
protocols. For RMSSD, a trend (p<0.1) for higher values after
12 weeks of therapy with MAD were found for forced breathing rates of 12 and for 15/min. Comparison of CPAP and MAD
results revealed no differences between treatment modalities.
With regard to mean systolic blood pressure, neither MAD
nor CPAP values differed from baseline values, and CPAP and
MAD comparisons showed no differences between treatment
modalities.
With MAD therapy, the mean blood pressure showed a
trend for lower values in all four applied forced breathing
patterns. With CPAP therapy, a significant fall became evident
in mean blood pressure under the condition of 6/min and of a
trend toward lower values under conditions of spontaneous
breathing and of 15/min. Comparison of CPAP and MAD
results disclosed no differences between treatment modalities
(Table 2).
With MAD therapy, diastolic blood pressure was significantly reduced by an average of 8.9 mmHg for spontaneous breathing (p < 0.05). Values were likewise reduced by an average of 7.3 mmHg for 6/min (p<0.05),
and a trend for lower values became evident for 12/min
as well as for 15/min. With CPAP therapy, diastolic
blood pressure was significantly reduced by an average
of 8.4 mmHg for spontaneous breathing (p<0.05) as well
as on average by 9.5 mmHg for 6/min (p<0.05). A trend
for lower values was apparent for 15/min. Comparison of
CPAP with MAD showed no differences between treatment modalities (Table 2, Fig. 3).
Frequency domain values: HRV, SBPV, and BRS
In comparison to baseline, mean HRV-LF values as well
as mean HRV-LF/HF values did not differ with either
MAD or CPAP therapy. These results consistently appeared for all four applied breathing patterns. After
Sleep Breath (2016) 20:635–646
12 weeks of MAD therapy, the HRV-HF component increased by 9.59 ms2 for 12/min (p<0.05) and showed a
trend toward higher values for 15/min. Only at forced
breathing at 6/min after use of CPAP did SBPV-LF
values increase by 0.324 mmHg2 (p <0.05); SBPV-LF/
HF values demonstrated a trend toward higher values.
In comparison to baseline mean values of SBPV-HF,
α-LF, α-HF, and α-tot differed neither with MAD
therapy nor with CPAP therapy. These results were
consistently found for all four applied breathing
patterns.
Comparison of CPAP with MAD revealed that there
were no differences between treatment modalities for all
parameters of HRV, SBPV, and BRS (Table 2).
Discussion
For the first time, the effects of 12-week CPAP and 12week MAD therapy on cardiovascular and autonomic
parameters during daytime were investigated, under conditions of controlled breathing. Both CPAP and MAD
therapy led to changes in blood pressure in patients
with mild to severe OSA. In addition, changes in
HRV values were observed for therapy with MAD. Both
CPAP and MAD therapy substantially eliminated breathing cessations, with an advantage for CPAP treatment.
These findings became evident regardless of the definition of efficacy and the severity of OSA and are in line
with previous studies dealing with this topic [12–14].
Additionally, CPAP improves REM and SWS sleep,
while MAD shows a significant effect on REM sleep
only. No effects of therapy were detected for total sleep
time, wake time after sleep onset, or sleep efficiency.
With regard to parameters for vagal autonomic activity, the HRV-HF component increased with 3 months of
MAD use, but not with CPAP. Similarly, a trend toward
greater HRV RMSSD values became apparent with
MAD use. Analysis of continuous blood pressure measurements from the cardiovascular autonomic function
test revealed changes in mean and diastolic pressures,
but not in systolic blood pressure. Diastolic blood pressure declined markedly with both CPAP and MAD
treatment. Mean blood pressure benefited from CPAP
treatment only.
No effects were detected on daytime blood pressure
as measured with the Riva-Rocci method.
Analysis of autonomic activity in the frequency domain showed no effects with either treatment modality.
Merely a minor effect on HRV-HF after MAD and on
SBPV-LF after CPAP was detected after various breathing frequencies. No effects on BRS were found.
643
We evidenced that both treatment options may improve daytime blood pressure, especially diastolic. Our
primary finding was accordingly that MAD is as effective as CPAP in improving parameters of daytime cardiac autonomic modulation, especially blood pressure.
This finding is surprising since the reduction of AHI
by MAD is less than with CPAP. With respect to efficiency, the results of our study are in agreement with
previous studies [15–20, 23]. We did not establish an
exclusion criterion related to the AHI. We studied patients with a mean AHI of 28.6 ± 16.5/h (min 10.8/h,
max 83.6/h), which is comparable to the other studies
cited. Engleman et al. [23] also included severe apneics
without restriction, whereas Aarab et al. [15], Ferguson
et al. [17], Gagnadoux et al. [18], and Lam et al. [21]
limited the AHI threshold to 40 to 60 events per hour
of sleep.
We recruited only n = 13 patients with severe sleep
apnea, which may be related to the fact that we are a
specialized university center with more co-morbid patients than in an outpatient sleep center. Although we
did not treat many severe patients, it is important to note
that the higher the AHI, the higher the effect of MAD on
the AHI is. In mild sleep apnea patients, we found a
decline of AHI by about only 40 %; in moderate patients, by 43 %; and in severe patients, by 60 %. It is
therefore evidently the case that, despite primary recommendation of MAD for mild to moderate OSA [2, 22], it
may also offer benefits for a subgroup of patients with
severe OSA. Some additional predictors may be supinepredominant OSA, younger age, female gender, less obesity, and certain craniofacial features [36].
The effect on sleep is comparable in both treatment
options and is limited to an improvement in REM sleep
for MAD and CPAP, and in SWS sleep for CPAP only,
which highlights another advantage of CPAP therapy. Although such benefits are not dramatic, this aspect should
be kept in mind when selecting patients for a special kind
of treatment. On the other hand, it is necessary to note
that the amount of SWS before treatment was within normal ranges—which limits a possible SWS rebound. REM
sleep was reduced during the baseline night, which justified expectation of a treatment effect.
With regard to cardiac autonomic modulation, some
effect has been shown until now only for CPAP [5, 8].
HRV is apparently a prominent marker for measuring
the effect of CPAP on the autonomic system [5, 8],
but some authors also reported a positive effect of
CPAP on BRS [9, 10]. These studies, however, are
not comparable owing to methodological differences involving time points at which measures were taken,
methods of detection, analysis methods, and duration
of treatment.
644
We determined such effects in the present study as well. We
could not detect blood pressure changes at daytime as objectified with the standard Riva-Rocci measurement, but we detected blood pressure changes with the Portapres method.
These changes were considerable. A blood pressure change
of about 7 to 9 mmHg is clinically significant in comparison to
the changes reported for CPAP treatment, which are much
lower [4]. In addition, these results are in line with data from
Phillips et al. [13] who also reported a change in diastolic
blood pressure after MAD treatment, and from Gotsopoulos
et al. [24] who reported a decrease in the 24 ambulatory blood
pressure monitoring (ABPM) mean after 4 weeks of MAD
treatment in comparison to sham MAD. Barnes et al. [16] also
found a decline after 3 months of treatment in diastolic ABPM
blood pressure, but only at nighttime in comparison to CPAP
and to placebo. In general, for CPAP treatment, changes in
systolic as well as in diastolic blood pressure were reported for
daytime as well as for nighttime, but with low effect magnitudes [4]. The effect is more pronounced in patients with
higher blood pressure and in patients with resistant hypertension [4]. In our study, we did not include patients with resistant
hypertension. We included three patients who were being
treated with antihypertensive medication.
The effects determined in our study would have possibly
been even more pronounced if we had included patients with
elevated blood pressure or resistant hypertension. A mean RR
of 122.8/79.7 mmHg at baseline indicated that the patients
were within normal blood pressure ranges or slightly higher.
It is also worthy of note, however, that the ambulatory
ABPM is not comparable to our short-time series measurement. Second, the influence of breathing on ABPM and on
our time series protocol can be different. We consequently
conducted a special breathing protocol with fixed breathing
frequencies. This allows a standardized comparison between
CPAP and MAD, but not with data evaluated without control
of respiration.
RMSSD improvement with the 3-month MAD treatment
also represents the positive effect of treatment on autonomic
tone. Nevertheless, it remains unclear why there are no significant changes after CPAP and why we could detect the changes with only two breathing frequencies (12/min and 15/min).
Surprisingly, BRS did not change at daytime after 3 months
of both CPAP and MAD therapy. In addition, only small
changes were seen in HRV-HF (with MAD) and in SBPVLF (with CPAP). Although the changes in HRV and SBPV
indicate positive treatment effects, it should be considered that
our patients were without elevated cardiovascular risk, and no
marked elevations of HRV, BPV, or BRS were present upon
selection inclusion. These circumstances do not favor either
therapy; they rather indicate that changes in these parameters
during daytime and an improvement in these parameters with
therapy were evident presumably only in patients with severe
sleep apnea or in patients with severe co-morbidities.
Sleep Breath (2016) 20:635–646
Distinguishing between OSA severity groups and/or occurrence of cardiovascular morbidities was outside the scope of
this trial. In total, only n=13 patients (33 %) suffered from
severe sleep apnea and were free of co-morbidities. This number is low to obtain statistical meaningful results. This should
be the subject for future investigation. Furthermore, it could be
assumed that there may be acute changes during the night due
to therapy.
MAD technique issues
The results of our study are specific for the device we used. It
must be noted that different MAD devices are not comparable
with respect to efficacy and in accordance with AHI and type
of protrusion [37]. We used a custom-made individual
bimaxillary appliance, the same that Phillips et al. [13] used.
In contrast to CPAP treatment—for which we assume that
device characteristics are similar when the same pressure is
applied—there are evidently relevant MAD device differences
[37].
In addition, a sufficient number of healthy teeth for anchorage are an important issue in selecting patients for treatment
with MAD. Whether patients with sufficient teeth differ from
other sleep apnea patients has not yet been clarified. When
recruiting patients for the study, many could not be included
owing to dental decay, morbid teeth, or an insufficient number
of teeth. Occasionally, this makes fitting a patient with a MAD
treatment more difficult and time consuming than the CPAP
treatment. Well-organized co-operation with educated and experienced dentists is necessary to realize a patient flow without many dropouts.
Study limitations
One limitation of this trial is that objective wear-time sensors
were not available; such devices were unfortunately not available for the MADs used for this trial. For CPAP it is reported
that compliance rates may influence changes in cardiac autonomic modulation [8] due to therapy; therefore, there is a need
to fit MADs with wear-time sensors. Recent developments in
oral appliances allow for such measures, for example, by enabling installation of an embedded micro sensor thermometer
[38]. To promote good and comparable compliance rates in
both treatment arms in the present trial, study participants
were seriously advised to use the therapy for at least 6 h per
night and for at least 6 days per week. Inadequate compliance
with the instructions resulted in n=3 dropouts during the
course of the study.
Another limitation of this crossover study is that the change
of treatment modality from MAD to CPAP or CPAP to MAD
was not accompanied by a washout period, i.e., no therapy for
a number of days. A recently published review by Vroegop
et al. [39] concluded that there is some evidence that CPAP
Sleep Breath (2016) 20:635–646
washout exists for some days in patients, although the intensity and duration remain unclear. Therefore, some influence of
the preceding CPAP therapy on the subsequent titration to
MAD could not be excluded. Comparison of therapy sequences MAD–CPAP with CPAP–MAD by statistical analysis, however, revealed no significant difference in results. After 12 weeks of therapy, this effect could consequently be
neglected. For design of future crossover studies on therapeutic interventions for OSA, a washout period should be
considered.
In conclusion, 12 weeks with MAD and with CPAP lead to
changes in cardiac autonomic modulation, in particular, by
lowering diastolic blood pressure. At the same time, both therapy modalities resulted in significant reductions in the number
of breathing cessations, with greater significance in CPAP.
645
6.
7.
8.
9.
10.
Funding The study was financially supported by an unrestricted grant,
and oral appliances were supplied by Somnomed Limited, Australia.
11.
Conflict of interest Thomas Penzel has received research grants from
ImThera Medical, Heinen and Loewenstein, Weinmann GmbH+Co. KG,
and Resmed Germany/Australia. Ingo Fietze has received research grants
from Hoffrichter GmbH, Philips/Respironics, and ResMed Germany Inc.
All other authors report no conflicts of interest. The authors alone are
responsible for the content and writing of the paper.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a link
to the Creative Commons license, and indicate if changes were made.
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