Department of Cardiology and Pneumology, Georg-August-Universität Göttingen, Robert-Koch-Str. 40, D-37099 Göttingen, Germany
Received 14 December 2004; revised 24 May 2005; accepted 26 May 2005; online publish-ahead-of-print 26 August 2005.
* Corresponding author. Tel: +49 551 3914141; fax: +49 551 3914142. E-mail address: larsluethje{at}med.uni-goettingen.de
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Abstract |
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Methods and results Ten patients with OSA on CPAP therapy were studied for three nights by polysomnography. 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 apnoeahypopnoea index was 41.0 h1 (12.066.6) at baseline and was significantly lower during CPAP [2.2 h1 (0.312.4)] compared with pacing [39.1 h1 (8.278.5)]. 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.
Key Words: Pacing Continuous positive airway pressure Sleep apnoea
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Introduction |
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The standard treatment for OSA is continuous positive airway pressure (CPAP), which improves nocturnal ventilation, reduces excessive daytime sleepiness, and improves the quality of life.7 In patients with heart failure, CPAP increases left ventricular ejection fraction.8 However, CPAP causes considerable patient discomfort, and long-term compliance, which lies around 6070%,9,10 depends highly on effective symptom relief.
The recent report of Garrigue et al.11 that nocturnal atrial overdrive pacing markedly reduced central and obstructive apnoea episodes in pacemaker patients was met with considerable enthusiasm because this might lead to a new and more convenient therapeutic concept. Two mechanisms by which pacing might exert its observed effect have been proposed.12 According to the first, overdrive pacing improves cardiac output and reduces pulmonary congestion with a consequent reduction of hyperventilation and central apnoea. The second hypothesis suggests that overdrive pacing counteracts nocturnal hypervagotonia and stabilizes respiration by acting on cardiac or sympathetic afferent neurons.
Neurohumoral markers [plasma and urinary norepinephrine, brain natriuretic peptide (BNP)]1315 are elevated in OSA and associated with left ventricular function and prognosis in heart failure.16,17 The heart rate increase induced by overdrive pacing might affect these humoral parameters.
The population studied by Garrigue et al.11 was not representative for patients with OSA, as they had not sought medical care because of suspected sleep-related breathing disorders, and all had an indication for pacing due to bradycardia. Moreover, most of the patients had predominantly central but not obstructive apnoea. To further elucidate the effects of atrial overdrive pacing on sleep-disordered breathing and humoral parameters, we studied a characteristic sample of patients with OSA and compared the two therapeutic interventions, CPAP and nocturnal atrial overdrive pacing with a temporary external pacemaker, in a random cross-over design.
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Methods |
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Protocol
At the beginning of the study, a detailed medical history was obtained and a thorough physical examination including electrocardiography (ECG), lung function, and echocardiography was performed. The patients underwent full-night polysomnography for three consecutive nights. The first night was without CPAP or pacing, and the data served as baseline. In the following nights, the patients were randomly assigned to either standard CPAP therapy or atrial overdrive pacing in a cross-over design. Randomization was accomplished by the use of 10 sealed envelopes, which were consecutively numbered. Five envelopes contained the word CPAP and other five envelopes contained the word pacing in a random order indicating the treatment method used during night 2.
For the CPAP night, the patients used their own masks and devices, whereas for the pacing night, a temporary pacing lead was inserted.
Polysomnography
Electroencephalogram, electrooculogram, electromyogram, and electrocardiogram were recorded as previously described.18 Airflow was recorded by nasal pressure, whereas thorax and abdominal wall motions were monitored by Respitrace, as described in detail subsequently. Arterial oxygen saturation (SaO2) was measured transcutaneously by pulse oximetry (Healthdyne Technologies Inc., Marietta, OH, USA). The polysomnogram was analysed visually with a computer system (ALICE IV, Heinen und Löwenstein, Bad Ems, Germany). An apnoea was considered obstructive when nasal flow was absent in the presence of abdominal or thoracic movements and central when movements were absent as well. A hypopnoea was defined as a fall in nasal airflow >50% of baseline. Respiratory events were counted only when they were of at least 10 s duration. Sleep stages and arousal were evaluated according to standard criteria.19
Ventilation
Respiratory rate and tidal volume were registered by respiratory inductive plethysmography (Respitrace Systems, Ambulatory Monitoring Inc., NY, USA) calibrated in supine and standing positions using the least-squares method as described previously.20 End-tidal pCO2 was monitored continuously by withdrawing expired gas from the nostrils (Datex Normocap, Helsinki, Finland). A 1 min period was evaluated once every hour during sleep stage 2 in a phase without apnoea or hypopnoea, and the data were averaged over the night.
Atrial pacing, Holter monitoring
A temporary bipolar atrial pacing lead (fixation with a screw, Model 6416, Medtronic Inc., Minneapolis, MN, USA) was inserted transvenously under sterile conditions. After puncture of the basilic or cephalic vein, the lead was advanced to the free wall of the right atrium and fixed with a screw at the tip of the lead. Lead contact was considered acceptable if the pacing threshold was 2 V at 0.5 ms with a temporary pacer (Model 5388, Medtronic Inc.). During the night, the temporary pacer was set to a frequency of 15 beats above the mean nocturnal heart rate determined during the first night by Holter monitoring (Lifecard CF, DelMar Reynolds Inc., Feucht, Germany). The pacing performance of the lead was verified by ECG monitoring. All patients were paced in an AAI mode. The next morning, the temporary pacing lead was removed and the patients were examined by echocardiography for the presence of pericardial effusion.
Humoral parameters
Urine collection for norepinephrine concentration determinations began after patients had voided prior to retiring and encompassed all urine passed during the night, including the first morning void on arising. Urine was collected in containers acidified with 4% HCl and stored at 4°C prior to analysis. Norepinephrine was measured by high-performance liquid chromatography and normalized to urinary creatinine.
Each morning, blood samples for analysis of N-terminal pro-brain natriuretic peptide (NT-proBNP) were drawn in lithium-heparin tubes and immediately centrifuged for 10 min at 10 000 r.p.m. The supernatant was stored at 80°C until analysis. NT-proBNP was determined by an electrochemoluminescence immunoassay (Elecsys pro-BNP sandwich immunoassay; Roche Diagnostics, Basel, Switzerland).
Statistical analysis
The primary endpoint was the AHI. Secondary endpoints were the apnoea index (AI), hypopnoea index (HI), the total sleep time (TST), light (S1+S2), deep (S3+S4), and rapid eye movement (REM) sleep stages in percentage of the TST, arousal index associated with respiratory events, respiratory rate, minute ventilation, partial pressure of carbon dioxide (pCO2), mean oxygen saturation, minimum oxygen saturation, time of oxygen saturation <90%, the concentration of NT-proBNP in plasma, and norepinephrine in urine. Results for each variable studied were analysed with a standard approach for cross-over studies.21 The Wilcoxon rank-sum test was used to compare the sum of each patient's measurements between the randomized arms to test for carry-over effect. If no significant carry-over effect was present, a Wilcoxon rank-sum test was used to compare the difference between CPAP and pacing measurement to test for confounding by systematic changes over time (period effect). If no significant period effect existed, the Wilcoxon signed-rank test was used for a paired comparison of treatments. If there was a significant period effect, the unpaired Wilcoxon rank-sum test was used on the differences 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 was considered significant.
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Results |
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Period effect and carry-over effect
Statistical analysis revealed three significant period effects: S1 and S2 sleep stages in percentage of TST, minute ventilation, and arousals associated with a respiratory event. This means that the value of these three characteristics is influenced by whether the treatment is received in the second or in the third night. In our analyses, this was taken into account by using appropriate tests for these characteristics. No significant carry-over effects were revealed.
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Discussion |
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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 heart failure. The characteristic of OSA was the proof of predominately obstructive events during polysomnography associated with daytime sleepiness and thus an indication for CPAP therapy. Furthermore, the patients were overweight, which is one of the major risk factors for sleep apnoea.22 However, the age of our patient population was slightly higher than in other studies investigating OSA. Episodes of cardiac bradyarrhythmias can be expected in up to 20% of severe sleep apnoea patients23; however, these bradycardiac episodes usually are reversible with CPAP therapy.2325 Thus, OSA is no indication for pacemaker implantation. In line with this, none of our patients had pacemaker implanted in contrast to the patient population of the Garrigue study.11 In that study, patients were investigated with a permanent dual pacemaker that had been implanted because of symptomatic bradycardia. This and other differing patient characteristics might explain the discrepant results of our study in contrast to those of Garrigue et al.,11 who reported a >50% reduction in the number of apnoea events during pacing.
Effects of pacing on sleep-disordered breathing
There are basically two interacting mechanisms that are responsible for nocturnal respiratory events: ventilatory control instability and upper airway anatomy and collapsibility.26 Purely obstructive apnoea is rather difficult to treat with drugs such as theophylline or serotonergic agents, which influence ventilatory control,27,28 but it responds excellently to mechanical therapy with CPAP. Central apnoea is more closely related to ventilatory control abnormalities and is amenable to treatment with drugs acting on ventilatory control.28
Two mechanisms have been hypothesized in the effort to explain the effects of nocturnal overdrive pacing on sleep-disordered breathing.11,12 The first of these suggests that pacing might counteract nocturnal hypervagotonia by influencing cardiac vagal or sympathetic afferent neurons.12 Indeed, pulmonary unmyelinated irritant receptors, such as J receptors, stimulate ventilation.29 However, whether cardiac afferents have an impact on ventilation is not known.11,27 Nevertheless, direct stimulation of the vagus nerve can aggravate OSA.30 The second hypothesis suggests that overdrive pacing might improve cardiac function, thus stabilizing ventilatory control11 as referred subsequently.
The patients studied by Garrigue et al.11 and those of our study differed clearly in the character of their apnoea events. The patients described in Garrigue's report had an index of 12 central apnoea episodes per hour, whereas this index was only 2.7 h1 in our patients. Furthermore, our patients had more severe disordered breathing (AHI 41.0 vs. 27.0 h1). Therefore, we suggest that typical obstructive apnoea is not affected by overdrive pacing. However, central apnoea or hypopnoea, conditions that are more strongly influenced by ventilatory control mechanisms, might be affected by pacing.
Another difference between our study and that of Garrigue et al.11 was that our patients did not have nocturnal bradycardia. Our patients had a mean heart rate of 63 min1 during the baseline night compared to 51 min1 in those of Garrigue et al.11 The acute haemodynamic effect of pacing is frequency dependent. In 1871, Bowditch described the positive cardiac forcefrequency relationship. Later, it was demonstrated that atrial pacing improved left ventricular contractility and diastolic filling.31 The effect of pacing depends on the basal heart rate. The same absolute increase in heart rate induced with pacing will yield a greater increase in cardiac output when the initial heart rate is lower than when it is higher.32 Thus, increasing heart rate via physiological pacing (AAI mode) increases stroke volume especially in bradycardic patients. The difference in nocturnal basal heart rate might thus contribute to the more pronounced effect of pacing in the study of Garrigue et al.11 Indeed, pacemaker implantation in six patients with pronounced bradycardia but normal ejection fraction was effective in alleviating CheyneStokes type respiration in an uncontrolled case series.33
A third difference relates to the fact that a number of patients studied by Garrigue et al.11 had heart disease. In the patient population investigated in this study, three patients suffered from coronary artery disease; however, none of our patients had clinical signs of heart failure. As discussed previously, it was postulated that overdrive pacing might exert its effect on sleep-disordered breathing by improving cardiac function, thus reducing pulmonary congestion in patients with heart failure.27 Pulmonary congestion activates pulmonary J receptors, thereby inducing hyperventilation with hypocapnia. This destabilizes ventilatory control and predisposes to central sleep apnoea.8,34 The concept that left ventricular function is a key mechanism for the occurrence of central apnoea is further supported by recent data35 showing that the incidence of central apnoea in patients with heart failure is reduced by the haemodynamic improvement following cardiac resynchronization therapy. In our patients, who have OSA but no clinical evidence of heart failure, pulmonary congestion was unlikely. Thus, pacing could not improve pulmonary congestion in our patients. Accordingly, atrial overdrive pacing did not result in a significant change in minute ventilation or end-tidal CO2.
As nocturnal pacing performed significantly worse than CPAP on sleep-disordered breathing in our patients, one can assume the same for sleep stages and arousals. However, temporary pacing did not seem to disturb sleep as reflected by the sleep quality during the pacing nights.
Our findings are corroborated by other studies recently published. Lüthje et al.36 report no significant effect of nocturnal atrial overdrive pacing on the AHI in OSA patients with pacemakers implanted because of bradycardia. Extending the period of nocturnal overdrive pacing to 1 week37 or to 1 month38 also did not show an improvement of sleep-related breathing disorders or sleep quality.
Neurohumoral activation
Sympathetic activity as measured by norepinephrine excretion or microneurography is increased in OSA and returns to normal with effective treatment.13,15 BNP is released primarily in response to ventricular myocyte stretching, as seen in congestive heart failure. BNP and NT-proBNP, the N-terminal portion of the high molecular weight BNP precursor, serve as prognostic markers in heart failure.17,39,40 The significantly higher NT-proBNP concentration during the pacing night compared with the CPAP night implies a more favourite effect of CPAP on left ventricular function. This is in line with the finding that CPAP therapy in patients with OSA can improve a reduced left ventricular systolic function.41 There was no significant difference in urinary norepinephrine concentrations between both treatment modalities, suggesting that there was no major negative impact on sympathetic tone.
Limitations
The primary limitation of this study was that it was not double-blinded. This approach was chosen to maximize patient safety: a double-blinded study would have required a fourth night with the pacing lead inserted but inactive. However, ventilatory, sleep, and biological markers were assessed by two observers blinded to subject and intervention. A second limitation was the use of calibrated respiratory thoracic inductance plethysmography. This method extrapolates qualitative measurements of chest wall motion to derive approximate quantitative measures of minute ventilation. It can detect changes in minute ventilation of 15%.20,42 Thus, minor effects on ventilation cannot be ruled out. Cardiac output was not evaluated: evaluation of cardiac output during sleep is either inaccurate or disturbs sleep. Only the acute effect of atrial overdrive pacing during one night with a temporary pacing lead has been evaluated. Thus, we cannot exclude long-term improvements with continuous pacing. Furthermore, slight effects might be counteracted by pain and uneasiness of the patients because of the temporary pacing lead. However, as discussed previously, evaluation of the time and quality of sleep during the pacing night do not indicate a disturbed sleep.
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Conclusion |
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Acknowledgements |
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Conflicts of interest: C.U. has received a grant from Medtronic, which was unrestricted for performance of the study (16 000 in 2003). S.A. has received a grant from Medtronic, which was unrestricted for performance of the study (16 000
in 2003).
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Footnotes |
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References |
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