Atrial overdrive pacing compared to CPAP in patients with ...

European Heart Journal (2005) 26, 2568–2575 Clinical research
doi:10.1093/eurheartj/ehi448

Atrial overdrive pacing compared to CPAP in patients
with obstructive sleep apnoea syndrome

Christina Unterberg{, Lars Lu¨thje*{, Julia Szych, Dirk Vollmann, Gerd Hasenfuß,

and Stefan Andreas

Department of Cardiology and Pneumology, Georg-August-Universita¨t Go¨ttingen, Robert-Koch-Str. 40, D-37099 Go¨ttingen,
Germany

Received 14 December 2004; revised 24 May 2005; accepted 26 May 2005; online publish-ahead-of-print 26 August 2005

KEYWORDS Aims Obstructive sleep apnoea (OSA) is associated with oxygen desaturation, blood pressure increase, Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 18, 2016
and neurohumoral activation, resulting in possible detrimental effects on the cardiovascular system.
Pacing; Continuous positive airway pressure (CPAP) is the therapy of choice for OSA. In a recent study, nocturnal
Continuous positive airway atrial overdrive pacing (pacing) reduced the severity of sleep apnoea in pacemaker patients. We
compared the effects of CPAP with those of pacing in patients with OSA but without pacemaker
pressure; indication or clinical signs of heart failure.
Sleep apnoea Methods and results Ten patients with OSA on CPAP therapy were studied for three nights by polysom-
nography. During the nights that followed a night without any treatment (baseline), the patients
were treated with CPAP or pacing in a random order. Pacing was performed with a temporary pacing
lead. The pacing frequency was 15 b.p.m. higher than the baseline heart rate. The apnoea–hypopnoea
index was 41.0 h21 (12.0–66.6) at baseline and was significantly lower during CPAP [2.2 h21 (0.3–12.4)]
compared with pacing [39.1 h21 (8.2–78.5)]. Furthermore, duration and quality of sleep were
significantly improved during CPAP when compared with pacing.
Conclusion Nocturnal atrial overdrive pacing is no alternative therapeutic strategy to CPAP for the
treatment of OSA in patients without clinical signs of heart failure and without conventional indication
for antibradycardia pacing.

Introduction and more convenient therapeutic concept. Two mechanisms
by which pacing might exert its observed effect have been
Obstructive sleep apnoea (OSA) is associated with arterial proposed.12 According to the first, overdrive pacing improves
hypertension,1 worsening of heart failure,2 and cardiac cardiac output and reduces pulmonary congestion with a con-
rhythm abnormalities3 and is independently related to sequent reduction of hyperventilation and central apnoea.
cardiac morbidity and mortality.4 The prevalence of sleep The second hypothesis suggests that overdrive pacing coun-
apnoea is high, with nearly 5% of women and 15% of men teracts nocturnal hypervagotonia and stabilizes respiration
between 30 and 60 years being affected.5 The observed by acting on cardiac or sympathetic afferent neurons.
increase in the number of obese individuals will cause a
further rise in the prevalence.6 Neurohumoral markers [plasma and urinary norepi-
nephrine, brain natriuretic peptide (BNP)]13–15 are elevated
The standard treatment for OSA is continuous positive in OSA and associated with left ventricular function and prog-
airway pressure (CPAP), which improves nocturnal venti- nosis in heart failure.16,17 The heart rate increase induced by
lation, reduces excessive daytime sleepiness, and improves overdrive pacing might affect these humoral parameters.
the quality of life.7 In patients with heart failure, CPAP
increases left ventricular ejection fraction.8 However, The population studied by Garrigue et al.11 was not repre-
CPAP causes considerable patient discomfort, and long- sentative for patients with OSA, as they had not sought
term compliance, which lies around 60–70%,9,10 depends medical care because of suspected sleep-related breathing
highly on effective symptom relief. disorders, and all had an indication for pacing due to brady-
cardia. Moreover, most of the patients had predominantly
The recent report of Garrigue et al.11 that nocturnal atrial central but not obstructive apnoea. To further elucidate
overdrive pacing markedly reduced central and obstructive the effects of atrial overdrive pacing on sleep-disordered
apnoea episodes in pacemaker patients was met with breathing and humoral parameters, we studied a characte-
considerable enthusiasm because this might lead to a new ristic sample of patients with OSA and compared the two
therapeutic interventions, CPAP and nocturnal atrial over-
* Corresponding author. Tel: þ49 551 3914141; fax: þ49 551 3914142. drive pacing with a temporary external pacemaker, in a
random cross-over design.
E-mail address: [email protected]
{ The first two authors contributed equally to the study.

& The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: [email protected]

Atrial pacing in sleep apnoea 2569

Methods Atrial pacing, Holter monitoring Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 18, 2016

Patient selection A temporary bipolar atrial pacing lead (fixation with a screw, Model
6416, Medtronic Inc., Minneapolis, MN, USA) was inserted transve-
Patients aged between 18 and 80 and with a body mass index nously under sterile conditions. After puncture of the basilic or
.25 kg/m2 were contacted via mail and telephone to participate cephalic vein, the lead was advanced to the free wall of the right
in the study if they fulfilled the following criteria: a history of atrium and fixed with a screw at the tip of the lead. Lead contact
full-night polysomnography and manual analysis in our sleep labora- was considered acceptable if the pacing threshold was 2 V at
tory because of daytime sleepiness (Epworth sleepiness scale more 0.5 ms with a temporary pacer (Model 5388, Medtronic Inc.).
than 10 points) with the result of an apnoea–hypopnoea index During the night, the temporary pacer was set to a frequency of
(AHI) .15 h21 with .50% obstructive events and a subsequent 15 beats above the mean nocturnal heart rate determined during
CPAP treatment at least 3 months prior to the study. Exclusion cri- the first night by Holter monitoring (Lifecard CF, DelMar Reynolds
teria were cardiac valve disease or valvular replacement, patients Inc., Feucht, Germany). The pacing performance of the lead was
with an indication for pacemaker implantation, decompensated verified by ECG monitoring. All patients were paced in an AAI
heart failure, chronic atrial arrhythmias, immunosuppression, preg- mode. The next morning, the temporary pacing lead was removed
nancy, a life expectancy of ,6 months, concurrent participation in and the patients were examined by echocardiography for the
another study, or non-compliance. The study complies with the presence of pericardial effusion.
Declaration of Helsinki and was approved by the local Ethics
Committee, and written informed consent was obtained from Humoral parameters
each patient.
Urine collection for norepinephrine concentration determinations
Protocol began after patients had voided prior to retiring and encompassed
all urine passed during the night, including the first morning void
At the beginning of the study, a detailed medical history was on arising. Urine was collected in containers acidified with 4% HCl
obtained and a thorough physical examination including electrocar- and stored at 48C prior to analysis. Norepinephrine was measured
diography (ECG), lung function, and echocardiography was per- by high-performance liquid chromatography and normalized to
formed. The patients underwent full-night polysomnography for urinary creatinine.
three consecutive nights. The first night was without CPAP or
pacing, and the data served as baseline. In the following nights, Each morning, blood samples for analysis of N-terminal pro-brain
the patients were randomly assigned to either standard CPAP natriuretic peptide (NT-proBNP) were drawn in lithium-heparin
therapy or atrial overdrive pacing in a cross-over design. tubes and immediately centrifuged for 10 min at 10 000 r.p.m. The
Randomization was accomplished by the use of 10 sealed envelopes, supernatant was stored at 2808C until analysis. NT-proBNP was
which were consecutively numbered. Five envelopes contained the determined by an electrochemoluminescence immunoassay
word ‘CPAP’ and other five envelopes contained the word ‘pacing’ (Elecsys pro-BNP sandwich immunoassay; Roche Diagnostics, Basel,
in a random order indicating the treatment method used during Switzerland).
night 2.
Statistical analysis
For the CPAP night, the patients used their own masks and
devices, whereas for the pacing night, a temporary pacing lead The primary endpoint was the AHI. Secondary endpoints were the
was inserted. apnoea index (AI), hypopnoea index (HI), the total sleep time (TST),
light (S1 þ S2), deep (S3 þ S4), and rapid eye movement (REM)
Polysomnography sleep stages in percentage of the TST, arousal index associated
with respiratory events, respiratory rate, minute ventilation,
Electroencephalogram, electrooculogram, electromyogram, and partial pressure of carbon dioxide (pCO2), mean oxygen saturation,
electrocardiogram were recorded as previously described.18 minimum oxygen saturation, time of oxygen saturation ,90%, the
Airflow was recorded by nasal pressure, whereas thorax and abdomi- concentration of NT-proBNP in plasma, and norepinephrine in
nal wall motions were monitored by Respitrace, as described in urine. Results for each variable studied were analysed with a stan-
detail subsequently. Arterial oxygen saturation (SaO2) was measured dard approach for cross-over studies.21 The Wilcoxon rank-sum test
transcutaneously by pulse oximetry (Healthdyne Technologies Inc., was used to compare the sum of each patient’s measurements
Marietta, OH, USA). The polysomnogram was analysed visually between the randomized arms to test for carry-over effect. If no
with a computer system (ALICE IV, Heinen und Lo¨wenstein, significant carry-over effect was present, a Wilcoxon rank-sum
Bad Ems, Germany). An apnoea was considered obstructive when test was used to compare the difference between CPAP and
nasal flow was absent in the presence of abdominal or thoracic pacing measurement to test for confounding by systematic
movements and central when movements were absent as well. A changes over time (period effect). If no significant period effect
hypopnoea was defined as a fall in nasal airflow .50% of baseline. existed, the Wilcoxon signed-rank test was used for a paired com-
Respiratory events were counted only when they were of at least parison of treatments. If there was a significant period effect, the
10 s duration. Sleep stages and arousal were evaluated according unpaired Wilcoxon rank-sum test was used on the differences
to standard criteria.19 between night 3 and night 2 measurements to test for a treatment
effect. All results are shown as median (range). A P-value ,0.05
Ventilation was considered significant.

Respiratory rate and tidal volume were registered by respiratory Results
inductive plethysmography (Respitrace Systems, Ambulatory
Monitoring Inc., NY, USA) calibrated in supine and standing positions Patients
using the least-squares method as described previously.20 End-tidal
pCO2 was monitored continuously by withdrawing expired gas from A total of 107 patients were eligible to participate in the
the nostrils (Datex Normocap, Helsinki, Finland). A 1 min period study. At the time of closure of the study, 65 patients
was evaluated once every hour during sleep stage 2 in a phase have been contacted via mail and telephone. Of these, 12
without apnoea or hypopnoea, and the data were averaged over have agreed to participate in the study and were admitted
the night. to our hospital. It was intended to include 20 patients in

2570 C. Unterberg et al.

the study. However, following a pre-defined interim analysis, during pacing with 31.5 and 22.7 h21 and decreased during Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 18, 2016
the study was closed early, after 10 patients, by the Ethics CPAP to 0.3 and 2.4 h21.
Committee because of a highly significant difference in the
primary endpoint. Thus, 10 patients completed the entire During CPAP therapy, the TST was significantly longer with
protocol of the study; there were no dropouts. Half of a shift from light to deep sleep stages and REM sleep when
the patients were treated with CPAP prior to pacing, compared with pacing (Table 4 ). In line with this, the
whereas the other half were treated in a reverse order. arousal index was significantly lower during CPAP night
The patients were mostly obese and had normal left than during pacing night (Table 4 ). As shown in Table 3, no
ventricular and pulmonary functions (Table 1 ). None of the significant difference was observed between pacing and
patients had a history of heart failure. Diuretics were CPAP therapies with regard to nocturnal ventilation, as
prescribed to one patient, beta-blockers to four, and reflected by the unchanged minute ventilation and pCO2.
ACE-Inhibitors/AT1-antagonists to five patients.
Norepinephrine and NT-proBNP
Heart rate
At baseline, plasma NT-proBNP was not elevated; con-
During the night with atrial pacing, effective stimulation centrations were significantly higher with pacing when
was verified by Holter-ECG (Table 2, Figure 1 ). The compared with CPAP (Table 3 ). In eight patients, the NT-
difference in mean heart rate between the pacing and base- proBNP was higher during pacing night than during CPAP
line nights was 14.5 b.p.m. (10–18). The minimum heart night, although the median was lower during pacing night
rate during the first night was 55.5 b.p.m. (43–65), for all patients (Table 3 ). The norepinephrine concen-
57.5 b.p.m. (43–73) during the CPAP night, and 63 b.p.m. trations were not significantly different during the different
(45–78) during the pacing night. The maximum heart rate treatment strategies (Table 3 ).
during the first night was 87.5 b.p.m. (57–119), 95 b.p.m.
(58–110) with CPAP, and 88.5 b.p.m. (71–110) with pacing. Period effect and carry-over effect
Sinus pauses longer than 2.5 s were not detected in any of
the patients. Statistical analysis revealed three significant period effects:
S1 and S2 sleep stages in percentage of TST, minute venti-
Respiratory events, ventilation, and sleep lation, and arousals associated with a respiratory event.
This means that the value of these three characteristics is
During the first night, all patients had an AHI of .10 h21 influenced by whether the treatment is received in the
(Figure 2, Table 2 ). Two patients had approximately equal second or in the third night. In our analyses, this was
numbers of central and obstructive apnoea events, with taken into account by using appropriate tests for these
obstructive apnoea indexes (oAIs) of 2.5 and 4.9 h21, characteristics. No significant carry-over effects were
respectively, and central apnoea indexes (cAIs) of 2.5 and revealed.
4.4 h21, respectively. The predominant type of apnoea in
the other eight patients was obstructive [oAI 7.0 h21 Discussion
(2.5–30.0), cAI 1.2 h21 (0.0–7.9)]. The primary endpoint
AHI was significantly higher during pacing when compared In this first report on a randomized cross-over study compar-
with CPAP (Figure 2, Table 2 ). The same was noted for the ing the acute effects of nocturnal atrial overdrive pacing
HI and AI, and also here the apnoea episodes were predomi- with CPAP, the potential new therapy pacing performed sig-
nantly obstructive (Table 2 ). In line with this, the oxygen nificantly worse than the current therapeutic gold standard
saturation was significantly higher during CPAP when com- CPAP in improving the primary endpoint AHI as well as sleep
pared with pacing (Table 3 ). Pacing also performed worse stages and arousals. Another novel finding was that markers
than CPAP in the two patients with approximately identical of neurohumoral activation were not affected by pacing.
oAI and cAI. In these patients, the AHI at baseline was
33.6 and 17.9 h21, which remained nearly unchanged The most important feature of our study, and its strength,
is that it was designed to test whether pacing is effective in
a characteristic population of OSA patients on CPAP therapy
but without pacemaker indication or clinical signs of

Table 1 Patient characteristics Patients with Patients with All patients
pacing on night 2 pacing on night 3 (n ¼ 10)
Gender (Male/female) (n ¼ 5) (n ¼ 5)
Age (years) 9/1
Left ventricular ejection fraction (%) 4/1 5/0 61 (50–69)
Body mass index (kg/m2) 56 (55–65) 64 (50–69) 55 (36–66)
Coronary artery disease (Number of patients) 65 (40–66) 55 (36–65) 33.0 (27.2–45.7)
Arterial hypertension (Number of patients) 34.8 (29.3–35.6) 29.6 (27.2–45.7) 3
Diabetes mellitus (Number of patients) 1 2 6
Vital capacity (L/min) 4 2 5
Forced expiratory volume in 1 s (L/s) 1 4 3.5 (1.9–4.5)
2.9 (2.7–4.5) 3.6 (1.9–4.1) 2.9 (1.4–3.6)
2.3 (2.1–3.6) 3.0 (1.4–3.5)

Atrial pacing in sleep apnoea 2571

P-value
0.002
0.002
0.002
0.078
0.002
0.002

Pacing
78.0

(58.0–89.0)
39.1

(8.2–78.5)
13.6

(2.9–59.8)
1.6

(0.0–9.9)
8.5

(2.9–51.9)
15.9

(5.3–36.1)

CPAP Figure 1 Mean nocturnal heart rate during baseline, CPAP, and pacing.
63.0 During the pacing night, the temporary pacer was set to 15 beats higher
than the mean nocturnal heart rate of baseline (AAI mode). The circles rep-
(47.0–75.0) resent the heart rate of every single patient.
2.2

(0.3–12.4)
0.4

(0.0–7.4)
0.3

(0.0–7.2)
0.0

(0.0–1.6)
1.4

(0.2–5.0)

All patients Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 18, 2016
Baseline

62.5
(47.0–74.0)

41.0
(12–66.6)

10.3
(5.0–47.3)

1.2
(0.0–7.9)

7.0
(2.5–30.0)

20.2
(7.5–55.3)

Pacing
74.0

(67.0–87.0)
22.7

(8.2–46.7)
7.4

(2.9–14.6)
1.3

(0.0–2.6)
4.9

(2.9–9.2)
13.8

(5.3–34.1)

Patients with pacing on night 3 CPAP
60.0

(58.0–71.0)
1.4

(0.3–4.6)
0.3

(0.2–0.6)
0.3

(0.1–0.4)
0.0

(0.0–0.3)
0.8

(0.2–4.1)

Baseline Figure 2 Effect of CPAP and pacing on the AHI. The circles represent the AHI
61.0 of every single patient.

(57.0–70.0) heart failure. The characteristic of OSA was the proof of
17.9 predominately obstructive events during polysomnography
associated with daytime sleepiness and thus an indication
(12.0–43.2) for CPAP therapy. Furthermore, the patients were over-
5.8 weight, which is one of the major risk factors for sleep
apnoea.22 However, the age of our patient population was
(5.0–9.6) slightly higher than in other studies investigating OSA.
0.6 Episodes of cardiac bradyarrhythmias can be expected in
up to 20% of severe sleep apnoea patients23; however,
(0.0–4.4) these bradycardiac episodes usually are reversible with
4.9 CPAP therapy.23–25 Thus, OSA is no indication for pacemaker
implantation. In line with this, none of our patients had
(2.5–5.3) pacemaker implanted in contrast to the patient population
12.1 of the Garrigue study.11 In that study, patients were investi-
gated with a permanent dual pacemaker that had been
(7.5–36.6) implanted because of symptomatic bradycardia. This and
other differing patient characteristics might explain the dis-
Pacing crepant results of our study in contrast to those of Garrigue
78.0 et al.,11 who reported a .50% reduction in the number of
apnoea events during pacing.
(58.0–89.0)
57.4 Effects of pacing on sleep-disordered breathing

(29.6–78.5) There are basically two interacting mechanisms that are
32.4 responsible for nocturnal respiratory events: ventilatory

(5.2–59.8)
1.9

(1.0–9.9)
21.4

(4.0–51.9)
18.8

(8.3–36.1)

Table 2 Heart rate and respiratory events CPAP 68.0 P-value is given for all patients (CPAP vs. pacing).
Patients with pacing on night 2 (47.0–75.0)

2.6
(0.8–12.4)

1.1
(0.0–7.4)

0.5
(0.0–7.2)

0.2
(0.0–1.6)

1.5
(0.4–5.0)

Baseline 66.0
(47.0–74.0)

57.9
(38.8–66.6)

38.4
(11.0–47.3)

1.8
(0.2–7.9)

10.9
(8.7–30.0)

20.7
(8.7–55.3)

Heart rate
(min21)

AHI (h21)
AI (h21)
cAI (h21)
oAI (h21)
HI (h21)

2572

Table 3 Nocturnal ventilation, CO2 and SaO2, humoral parameters Patients with pacing on night 3 All patients P-value
Patients with pacing on night 2

Baseline CPAP Pacing Baseline CPAP Pacing Baseline CPAP Pacing

Respiratory rate (min21) 17.0 15.4 16.3 15.6 16.1 16.3 16.0 16.1 16.3 0.375
Minute ventilation (L/min) (14.5–26.3) (14.1–24.0) (15.6–24.5) (14.4–18.0) (13.6–17.3) (13.2–18.4) (14.4–26.3) (13.6–24.0) (13.2–24.5) 0.421
pCO2 (mmHg) 0.496
SaO2 mean (%) 5.0 4.4 6.6 5.2 6.0 5.8 5.1 5.4 6.3 0.008
SaO2 min (%) (3.9–7.1) (4.3–7.9) (6.2–9.8) (3.6–6.3) (4.1–6.4) (3.7–8.1) (3.6–7.1) (4.1–7.9) (3.7–9.8) 0.002
SaO2 ,90% (%TST) 0.002
NT-proBNP (pg/mL) 40.0 38.3 39.4 39.3 40.0 39.2 39.9 38.7 39.3 0.021
Norepinephrine (39.5–40.7) (37.3–40.0) (36.7–41.0) (37.5–40.0) (29.4–42.3) (37.4–42.6) (37.5–40.7) (29.4–42.3) (36.7–42.6) 0.547

(nmol/mmol crea) 90 93 91 93 94 92 92 94 92
(89–93) (91–95) (89–92) (92–94) (93–96) (91–94) (89–94) (91–96) (89–94)

68 86 71 78 89 76 75 88 74
(54–80) (83–93) (50–79) (62–86) (88–92) (58–86) (54–86) (83–93) (50–86)

37.2 5.9 36.4 7.1 0.3 17.4 20.4 0.3 22.1
(8.9–56.1) (0.0–17.7) (17.6–49.4) (0.7–20.6) (0.0–5.0) (0.7–23.6) (0.7–56.1) (0.0–17.7) (0.7–49.4)

117.3 77.2 88.9 260.5 117.5 160.0 154.4 117.5 99.5
(11.5–226.6) (9.7–202.2) (18.0–337.3) (19.3–526.2) (9.5–220.1) (16.8–341.7) (11.5–526.2) (9.5–220.1) (16.8–341.7)

23.0 19.3 24.0 15.1 14.0 13.2 17.3 15.9 16.0
(13.0–29.3) (14.5–29.7) (10.3–32.6) (8.9–19.0) (8.4–17.3) (11.2–17.4) (8.9–29.3) (8.3–29.7) (10.3–32.6)

PCO2, end-tidal partial pressure of carbon dioxide; SaO2 mean, mean oxygen saturation during the night; SaO2 min, minimum oxygen saturation; SaO2 , 90%, oxygen saturation below 90%; crea, creatinine; NT-proBNP,
N-terminal pro-brain natriuretic peptide, measurement in blood samples at the end of the nights. Norepinephrines measured in overnight urine. P-value is given for all patients (CPAP vs. pacing). The P-value for minute
ventilation is from a Wilcoxon rank-sum test on the differences (night 3 and night 2); all other P-values are from a paired Wilcoxon signed-rank test.

C. Unterberg et al.

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Atrial pacing in sleep apnoea 2573

P-value 0.004 S1 þ S2, sleep stages 1 and 2; S3 þ S4, sleep stages 3 and 4; arousal, arousal with respiratory event index. P-value is given for all patients (CPAP vs. pacing). P-values for S1 þ S2 and for arousal are from a Wilcoxon rank- control instability and upper airway anatomy and collapsibi-
0.016 sum test on the differences (night 3 and night 2); all other P-values are from a paired Wilcoxon signed-rank test. lity.26 Purely obstructive apnoea is rather difficult to treat
0.037 with drugs such as theophylline or serotonergic agents,
0.014 which influence ventilatory control,27,28 but it responds
0.008 excellently to mechanical therapy with CPAP. Central
apnoea is more closely related to ventilatory control
Pacing 320 abnormalities and is amenable to treatment with drugs
(280–376) acting on ventilatory control.28

85.0 Two mechanisms have been hypothesized in the effort to
(59.1–99.2) explain the effects of nocturnal overdrive pacing on sleep-
disordered breathing.11,12 The first of these suggests that
3.2 pacing might counteract nocturnal hypervagotonia by influ-
(0.0–15.3) encing cardiac vagal or sympathetic afferent neurons.12
Indeed, pulmonary unmyelinated irritant receptors, such
10.5 as J receptors, stimulate ventilation.29 However, whether
(0.5–27.7) cardiac afferents have an impact on ventilation is not
known.11,27 Nevertheless, direct stimulation of the vagus
13.6 nerve can aggravate OSA.30 The second hypothesis suggests
(1.5–50.8) that overdrive pacing might improve cardiac function, thus
stabilizing ventilatory control11 as referred subsequently.
CPAP 378
(293–419) The patients studied by Garrigue et al.11 and those of our
study differed clearly in the character of their apnoea
69.4 events. The patients described in Garrigue’s report had an
(56.7–78.0) index of 12 central apnoea episodes per hour, whereas this
index was only 2.7 h21 in our patients. Furthermore, our
9.6 patients had more severe disordered breathing (AHI 41.0
(0.6–22.4) vs. 27.0 h21). Therefore, we suggest that typical obstructive
apnoea is not affected by overdrive pacing. However,
21.6 central apnoea or hypopnoea, conditions that are more
(11.4–28.6) strongly influenced by ventilatory control mechanisms,
might be affected by pacing.
0.2
(0.0–1.6) Another difference between our study and that of
Garrigue et al.11 was that our patients did not have noctur-
All patients Baseline 291 nal bradycardia. Our patients had a mean heart rate of Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 18, 2016
(211–382) 63 min21 during the baseline night compared to 51 min21 in
those of Garrigue et al.11 The acute haemodynamic effect
88.1 of pacing is frequency dependent. In 1871, Bowditch
(70.9–99.5) described the positive cardiac force–frequency relationship.
Later, it was demonstrated that atrial pacing improved left
0.2 ventricular contractility and diastolic filling.31 The effect
(0.0–13.5) of pacing depends on the basal heart rate. The same
absolute increase in heart rate induced with pacing will
8.4 yield a greater increase in cardiac output when the initial
(0.0–18.1) heart rate is lower than when it is higher.32 Thus, increasing
heart rate via physiological pacing (AAI mode) increases
17.9 stroke volume especially in bradycardic patients. The
(1.7–75.8) difference in nocturnal basal heart rate might thus
contribute to the more pronounced effect of pacing in the
Pacing 320 study of Garrigue et al.11 Indeed, pacemaker implantation
(302–357) in six patients with pronounced bradycardia but normal
ejection fraction was effective in alleviating Cheyne–Stokes
79.3 type respiration in an uncontrolled case series.33
(59.1–88.4)
A third difference relates to the fact that a number of
4.7 patients studied by Garrigue et al.11 had heart disease. In
(0.2–15.3) the patient population investigated in this study, three
patients suffered from coronary artery disease; however,
11.1 none of our patients had clinical signs of heart failure. As
(6.0–27.7) discussed previously, it was postulated that overdrive
pacing might exert its effect on sleep-disordered breathing
6.2 by improving cardiac function, thus reducing pulmonary
(1.5–14.0) congestion in patients with heart failure.27 Pulmonary con-
gestion activates pulmonary J receptors, thereby inducing
Patients with pacing on night 3 CPAP 380 hyperventilation with hypocapnia. This destabilizes
(337–401)

69.0
(64.0–75.8)

9.5
(2.3–12.7)

21.6
(11.4–27.0)

0.2
(0.0–0.5)

Baseline 289
(211–382)

85.0
(70.9–90.3)

1.7
(0.0–13.5)

11.9
(7.8–18.1)

3.8
(1.7–18.3)

Pacing 326
(280–376)

85.5
(82.9–99.2)

0.3
(0.0–10.5)

6.4
(0.5–13.6)

36.9
(13.2–50.8)

Table 4 Sleep duration and quality CPAP 368
Patients with pacing on night 2 (293–419)

75.6
(56.7–78.0)

9.8
(0.6–22.4)

19.8
(11.5–28.6)

0.2
(0.0–1.6)

Baseline 293
(213–374)

94.9
(85.9–99.5)

0.0
(0.0–4.7)

4.4
(0.0–8.9)

33.2
(17.5–75.8)

TST (min)
S1 þ S2 (%TST)
S3 þ S4 (%TST)
REM (%TST)
Arousal (h21)

2574 C. Unterberg et al.

ventilatory control and predisposes to central sleep term improvements with continuous pacing. Furthermore, Downloaded from http://eurheartj.oxfordjournals.org/ by guest on March 18, 2016
apnoea.8,34 The concept that left ventricular function is a slight effects might be counteracted by pain and uneasiness
key mechanism for the occurrence of central apnoea is of the patients because of the temporary pacing lead.
further supported by recent data35 showing that the inci- However, as discussed previously, evaluation of the time
dence of central apnoea in patients with heart failure is and quality of sleep during the pacing night do not indicate
reduced by the haemodynamic improvement following a disturbed sleep.
cardiac resynchronization therapy. In our patients, who
have OSA but no clinical evidence of heart failure, pulmo- Conclusion
nary congestion was unlikely. Thus, pacing could not improve
pulmonary congestion in our patients. Accordingly, atrial Nocturnal atrial overdrive pacing is no alternative thera-
overdrive pacing did not result in a significant change in peutic strategy to CPAP for the treatment of OSA in patients
minute ventilation or end-tidal CO2. without clinical signs of heart failure and without conven-
tional indication for antibradycardia pacing.
As nocturnal pacing performed significantly worse than
CPAP on sleep-disordered breathing in our patients, one Acknowledgements
can assume the same for sleep stages and arousals.
However, temporary pacing did not seem to disturb sleep Dr Lu¨thje and Dr Unterberg contributed equally to the study. We
as reflected by the sleep quality during the pacing nights. thank Mrs Ko¨hler and Mr Gerritse for their statistical support. This
investigator-initiated study was supported by Medtronic Inc.,
Our findings are corroborated by other studies recently Minneapolis, MN, USA.
published. Lu¨thje et al.36 report no significant effect of
nocturnal atrial overdrive pacing on the AHI in OSA patients Conflicts of interest: C.U. has received a grant from Medtronic,
with pacemakers implanted because of bradycardia. which was unrestricted for performance of the study (16 000 E in
Extending the period of nocturnal overdrive pacing to 1 2003). S.A. has received a grant from Medtronic, which was unrest-
week37 or to 1 month38 also did not show an improvement ricted for performance of the study (16 000 E in 2003).
of sleep-related breathing disorders or sleep quality.
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