pii: sp-00516-14
http://dx.doi.org/10.5665/sleep.4746
NEURAL RESPIRATORY DRIVE AND AROUSAL
Neural Respiratory Drive and Arousal in Patients with Obstructive Sleep Apnea Hypopnea Si-Chang Xiao, Msc1,*; Bai-Ting He, MB1,*; Joerg Steier, PhD2,3; John Moxham, MD3; Michael I. Polkey, PhD4; Yuan-Ming Luo, PhD1 State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China; 2Lane Fox Respiratory Unit, Sleep Disorders Centre, Guy’s & St Thomas’ NHS Foundation Trust, London, UK; 3Department of Respiratory Medicine, King’s College London School of Medicine, London, UK; 4NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London, UK; *co-first authors 1
Study Objectives: It has been hypothesized that arousals after apnea and hypopnea events in patients with obstructive sleep apnea are triggered when neural respiratory drive exceeds a certain level, but this hypothesis is based on esophageal pressure data, which are dependent on flow and lung volume. We aimed to determine whether a fixed threshold of respiratory drive is responsible for arousal at the termination of apnea and hypopnea using a flow independent technique (esophageal diaphragm electromyography, EMGdi) in patients with obstructive sleep apnea. Setting: Sleep center of state Key Laboratory of Respiratory Disease. Patients: Seventeen subjects (two women, mean age 53 ± 11 years) with obstructive sleep apnea/hypopnea syndrome were studied Methods: We recorded esophageal pressure and EMGdi simultaneously during overnight full polysomnography in all the subjects. Measurements and Results: A total of 709 hypopnea events and 986 apnea events were analyzed. There was wide variation in both esophageal pressure and EMGdi at the end of both apnea and hypopnea events within a subject and stage 2 sleep. The EMGdi at the end of events that terminated with arousal was similar to those which terminated without arousal for both hypopnea events (27.6% ± 13.9%max vs 29.9% ± 15.9%max, P = ns) and apnea events (22.9% ± 11.5%max vs 22.1% ± 12.6%max, P = ns). The Pes at the end of respiratory events terminated with arousal was also similar to those terminated without arousal. There was a small but significant difference in EMGdi at the end of respiratory events between hypopnea and apnea (25.3% ± 14.2%max vs 21.7% ± 13.2%max, P < 0.05]. Conclusions: Our data do not support the concept that there is threshold of neural respiratory drive that is responsible for arousal in patients with obstructive sleep apnea. Keywords: arousal, OSA, hypopnea, diaphragm EMG, esophageal pressure Citation: Xiao SC, He BT, Steier J, Moxham J, Polkey MI, Luo YM. Neural respiratory drive and arousal in patients with obstructive sleep apnea hypopnea. SLEEP 2015;38(6):941–949.
INTRODUCTION Obstructive sleep apnea (OSA) is characterized by repeated episodes of apnea and hypopnea during sleep and major pathophysiological features of OSA are intermittent hypoxia and frequent arousals. Recurrent arousals prevent consolidated sleep and it has been shown that daytime sleepiness in patients with OSA is more closely related to arousal than to hypoxia indices.1 Recent studies have also suggested that arousal could interfere with the ability to effectively recruit the upper airway dilator muscles and may precipitate further obstructive respiratory events.2–4 Thus investigating the mechanism of arousal is important to further understand the pathophysiological changes of obstructive sleep apnea and to facilitate development of new approaches for relevant treatment options.5 Several studies have argued, based on recordings of esophageal pressure (Pes) during overnight polysomnography,6,7 that there is an arousal threshold of respiratory effort triggering arousal in patients with OSA. However, Pes is affected by changes in lung volume, particularly airflow,8–10 and this fundamental physiological property could preclude accurate
evaluation of neural respiratory drive in patients with OSA, which is characterized by change in airflow. We have previously shown that while EMGdi relates closely to Pes during apnea, this is not so once airflow resumes following an apnea9 because pressure generation declines with increase in airway flow. It remains unclear whether the stimulus leading to arousal from sleep during obstructive apneas and hypopneas is related to central respiratory output.4,11 Diaphragm electromyography (EMGdi) recorded from a multi-pair esophageal electrode can accurately assess neural respiratory drive.8–10,12 If the hypothesis that neural respiratory output causes arousal was correct, a given level of respiratory drive within a given stage of sleep and therefore sleep depth should reliably trigger arousal during either apnea or hypopnea events, and the converse should also apply—specifically that arousal should not occur unless neural respiratory drive exceeds a certain threshold. Since most patients with obstructive sleep apneahypopnea syndrome present with a mixture of apneas and hypopneas, we reasoned that the untreated sleep apnea patient provides an ideal “experiment of nature” to test this hypothesis.
Submitted for publication August, 2014 Submitted in final revised form October, 2014 Accepted for publication November, 2014 Address correspondence to: Y.M. Luo, PhD, Professor of Respiratory Medicine, State Key Laboratory of Respiratory Disease, 151 Yanjiang Road, Guangzhou 510120, China; Tel: 0086 20 3429 4087; Email: [email protected]
METHODS Seventeen subjects aged 37 to 76 years (2 females and 15 males, mean age 53 ± 11 years, BMI 26.4 ± 3.7 kg/m2 ) with OSA were recruited from patients referred to the sleep center of Guangzhou Institute of Respiratory Disease, China; their demographic data are shown in Table 1. Patients were advised to abstain from alcohol and sedative medicines ≥ 24 h prior to the study. No patient had significant coexisting conditions
SLEEP, Vol. 38, No. 6, 2015
941
Neural Respiratory Drive and Arousal—Xiao et al.
Table 1—Anthropometric and polysomnographic data. Subject Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mean SD
Age, years 55 38 57 66 44 65 40 43 57 56 76 59 37 52 62 45 51 53.1 10.9
Sex M M M F M F M M M M M M M M M M M – –
Height, m 1.61 1.86 1.71 1.53 1.66 1.47 1.65 1.73 1.70 1.70 1.57 1.68 1.75 1.67 1.60 1.60 1.75 1.66 0.09
Weight, kg 69.5 88 84 58 79 68 90 87 65 77 50.5 73 84 65 72 70 58 72.8 11.6
AHI 42.6 54.0 49.4 28.0 42.6 61.9 48.1 58.9 23.0 21.9 47.5 60.3 68.5 44.3 72.5 53.0 22.9 47.0 15.7
Sleep Efficiency 78% 90% 98% 55% 94% 73% 85% 94% 73% 74% 90% 80% 89% 77% 83% 89% 78% 82.4% 10.6%
Maximal EMGdi Recording Immediately prior to lights off, the maximal EMGdi was recorded from a series of maximal inspiratory maneuvers including maximum sniff efforts from functional residual capacity, maximal isovolumetric inspiratory contraction at FRC (Mueller maneuver), and maximal inspiration from FRC to total lung capacity. Each maneuver was performed in the supine position and repeated until 3 maximal and reproducible values were obtained. There was a minimum period of 1 min of rest between the different maneuvers. The maximum was defined as the highest level of EMGdi observed during any of these 3 maneuvers.
(such as neuromuscular disease) that were likely to affect respiratory muscle function. The study was approved by the ethics committee of The First Affiliated Hospital of Guangzhou Medical University, and all subjects gave their informed consent. Esophageal Electrode and Its Positioning The EMGdi was recorded from a balloon-electrode catheter (Yinghui Medical Equipment and Scientific Ltd, Guangzhou, China) as previously described (for further details please refer to the supplemental material, Figure S1).12 Briefly, the catheter with 10 electrodes (which formed 5 pairs) was passed through the nose and was swallowed into the esophagus. It was positioned close to the electrically active region of the diaphragm based on spontaneous EMGdi recorded from the 5 pairs of electrodes in the supine position.12 The catheter was securely taped at the nose. The EMGdi signals were amplified and band-pass filtered between 20 Hz and 1 kHz (Yinghui Medical Equipment of Scientific Ltd., Guangzhou, China). The balloon was connected to a pressure transducer (DP 15 Validyne, Northridge, CA, USA) to measure Pes.
Data Analysis Data were analyzed off-line. Arousal was defined, per convention, as an abrupt shift in the EEG lasting > 3 seconds.13 Respiratory event related arousal was defined as resumption of airflow and development of arousal at the same time (e.g., within a breathing cycle). The root mean square (RMS) of the raw signal of the EMGdi was calculated by computer using a time constant of 100 ms. The RMS reported was that from the electrode pair with the largest EMGdi amplitude for each breathing cycle. To avoid artifactual interference from the electrocardiogram, RMS was measured from the segments between QRS complexes. An obstructive apnea was defined as absence of airflow > 10 sec while there was ongoing phasic inspiratory EMGdi. An obstructive hypopnea was defined as reduction of airflow > 30% for > 10 sec associated with ≥ 3% desaturation or the event being associated with arousal.13 Obstructive apneas and hypopneas were selected for further analysis in stage 2 and REM sleep restricted to the supine position. To minimize the effect of sleep times on the arousal threshold, apneas and hypopneas events adjoining each other were selected. We arbitrarily divided each respiratory event into 3
Recording of Polysomnography, Pes, and EMGdi Conventional polysomnography including electroencephalogram (EEG) (C3-A2, C4-A1), left and right electro-oculograms (EOG), submental electromyogram (EMGchin), airflow recorded from a pneumotachograph (10 subjects) or pressure and thermal sensors (7 subjects), snoring, body position, and oxygen saturation was undertaken overnight using a Powerlab recording system (ADInstruments, Castle Hill, Australia). In addition to the conventional polysomnography, Pes and 5 pairs of EMGdi were recorded during overnight polysomnography. The sample frequency was 2 kHz for EMGdi and 200 Hz for other signals. SLEEP, Vol. 38, No. 6, 2015
BMI, kg/m2 26.8 25.4 28.7 24.8 28.7 31.5 33.1 29.1 22.5 26.6 20.5 25.9 27.4 23.3 28.1 27.3 18.9 26.4 3.7
942
Neural Respiratory Drive and Arousal—Xiao et al.
Neural Respiratory Drive at the End of Respiratory Events Terminated with or without Arousal during Stage 2 Sleep The majority of respiratory events were terminated with arousal, and in 5 subjects, all respiratory events were terminated
sections: the beginning which included the first respiratory effort without airflow, the middle which was between the first and the last obstructed breath, and the end which contained the last respiratory effort before arousal and resumption of airflow. Data are presented as mean ± SD, and a paired t-test was applied for examining statistical differences between hypopnea and apnea events. An ANOVA and a post hoc StudentNewman-Keuls test were performed to test the difference in neural respiratory drive over the respiratory events. RESULTS Variability of Esophageal Pressure and Diaphragm EMG during Stage 2 Sleep A total of 986 obstructive apneas and 709 hypopneas were analyzed when supine in sleep stage N2. The EMGdi at the end of an apnea was lower than that recorded at the end of a hypopnea events (21.7% ± 13.2%max vs 25.3% ± 14.2%max, P < 0.05; Figure 1). There was a wide variation in the level of EMGdi at the end of apneas and hypopneas within individual subjects (Figure 2). The mean coefficient of variation (CV) of the EMGdi at the end of arousal related events was 29% ± 8% for apnea and 29% ± 7% for hypopnea (Table 2). The mean value of Pes for all the subjects was similar between apnea and hypopnea events (29.0 ± 12.6 cm H2O vs 27.5 ± 12.4 cm H2O, P = ns; Table 2). However, there was substantial variation in Pes at the end of apneas and hypopneas within individual subjects (Figure 2) and the CV of Pes at the end of arousal related events was 25% ± 10% for apneas and 23% ± 9%for hypopnea (Table 2).
Figure 1—Comparison of the diaphragm EMG at the end of respiratory events (apnea and hypopnea). EMGdi at the end of the hypopnea is significantly larger than that observed during the apnea (P < 0.05). Each dot represents the mean for one subject.
Table 2—Comparison of esophageal pressure and EMGdi between hypopnea and OSA at the end of events.
Subject Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mean SD
Esophageal Pressure Hypopnea OSA Mean CV Mean CV 35.1 18% 40.8 16% 15.9 40% 17.1 45% 42.1 16% 44.5 21% 24.2 25% 33.7 29% 19.5 34% 17.5 31% 34.7 17% 36.1 19% 41.5 21% 36.3 21% 37.5 15% 39.0 23% 20.2 18% 25.4 18% 24.1 30% 27.9 17% 32.2 17% 34.4 17% 46.8 9% 47.4 8% 11.1 38% 9.0 50% 11.4 23% 12.0 32% 42.9 29% 42.0 27% 20.1 15% 18.8 19% 8.8 27% 11.7 24% 27.5 23% 29.0 25% 12.4 9% 12.6 10%
EMGdi (%max) Hypopnea OSA Mean CV Mean 40.1 25% 38.8 17.1 34% 14.3 41.7 19% 36.6 19.0 54% 13.5 14.8 28% 12.1 27.3 23% 28.5 26.3 33% 21.0 25.8 29% 16.0 18.2 25% 18.1 22.9 27% 18.4 22.3 26% 19.1 59.1 19% 56.8 15.9 30% 14.6 11.3 33% 11.7 48.4 34% 34.2 14.9 30% 8.7 5.6 22% 6.2 25.3 29% 21.68* 14.2 8% 13.2
CV 23% 39% 28% 33% 24% 28% 36% 32% 23% 34% 31% 23% 34% 41% 31% 23% 15% 29% 7%
*P < 0.05 EMGdi for hypopnea is significant higher than that for OSA. CV, coefficient of variation. SLEEP, Vol. 38, No. 6, 2015
943
Neural Respiratory Drive and Arousal—Xiao et al.
Figure 2—There is a wide variation in diaphragm EMG (A) and esophageal pressure (B) recordings at the end of apneas and hypopneas within an individual subject (data derived from subject 7).
Table 3—Esophageal pressure and diaphragm EMG at the end of the hypopnea and apnea events with and without arousal.
Subject Number 1 3 4 8 9 13 14 15 Mean SD
Pes (cmH2O) Hypopnea OSA With Without With Without 35.1 40.7 40.8 41.7 42.2 43.4 44.5 39.4 24.2 27.7 33.7 29.3 37.5 36.7 39.1 38.2 20.2 21.4 25.4 25.4 11.1 13.5 9.0 8.9 11.4 9.8 12.0 8.2 42.9 44.3 42.1 47.1 28.1 29.7 30.8 29.8 13.1 13.6 13.9 14.8
by an arousal from sleep, but a minority of hypopnea events (15.5% ± 14.2%) and apnea events (9.5% ± 11.6%) were terminated without arousal. The mean EMGdi at the end of obstructive respiratory events that terminated with arousal was similar to that terminated without arousal (22.9% ± 11.5%max vs 22.1% ± 12.6%max for apneas, P = ns; 27.6% ± 13.9%max vs 29.9% ± 15.9%max for hypopneas, P = ns; Table 3, Figure 3). Similarly, Pes at the end of obstructive respiratory events that terminated with arousal was similar to those terminated without arousal (30.8 ± 13.9 cm H2O vs 29.8 ± 14.8 cm H2O for apneas, P = ns; 28.1 ± 13.1 cm H2O vs 29.7 ± 13.6 cm H2O for hypopneas, P = ns; Table 3).
was observed, if present, at the end rather than at the middle of the apnea or hypopnea events. Changes in Pes over the course of apneas and hypopneas associated with arousal were similar to changes in EMGdi (Table 4 and Figure 4). EMGdi during sleep immediately before apnea was sometimes larger than that at the end of apnea (Figure 4). In some subjects (n = 4), EMGdi over the course of hypopneas was larger than that at the end of apneas (Figure 5 and Figure S2, supplemental material). Neural Respiratory Drive at the End of Apnea and Hypopnea Events at Different Sleep Times during Stage 2 Sleep Respiratory drive at the end of apnea and hypopnea events during the first 3 h of sleep was the same as that during the last 3 h of sleep, as assessed by Pes (28.5 ± 12.4 cm H2O vs 27.2 ± 12.2 cm H2O, P = ns) and EMGdi (21.5 ± 13.0%max vs 22.4 ± 13.3%max, P = ns).
Change of Neural Respiratory Drive over the Course of Apneas and Hypopneas Associated with Arousal Neural respiratory drive, whether assessed by Pes or EMGdi at the end of an apnea event was usually higher than that at the beginning or middle of an obstructive respiratory event, but this was not always the case (Figure 4). EMGdi during the middle of each event was higher than that at the end of the event in 12% ± 11% of apneas and 34% ± 18% of hypopneas, but arousal SLEEP, Vol. 38, No. 6, 2015
EMGdi (%max) Hypopnea OSA With Without With Without 40.1 44.6 38.8 37.6 41.7 49.3 36.6 34.8 19.0 22.4 13.5 10.8 25.8 21.8 16.0 16.6 18.2 17.5 18.1 18.1 15.9 20.9 14.7 15.1 11.3 11.1 11.7 6.3 48.4 51.6 34.2 37.5 27.6 29.9 22.9 22.1 13.9 15.9 11.5 12.6
Neural Respiratory Drive during Apnea and Hypopnea Events during REM Unlike neural respiratory drive during stage 2, neural drive appeared highly variable and did not increase gradually over 944
Neural Respiratory Drive and Arousal—Xiao et al.
Figure 3—The mean of the esophageal pressure (A) and diaphragm EMG (B) at the end of apneas that were associated with arousal from sleep are similar to those without arousal (data derived from subject 8).
the course of the apnea or hypopnea events during REM sleep. Pes and EMGdi at the middle of an obstructive respiratory event were sometimes larger than those at the end of the apnea and hypopnea event, although arousal commonly developed immediately after apnea or hypopnea (Figure 6).
Table 4—Percentage of events whose esophageal pressure or EMGdi from one of the event is larger than those at the end of the event. Subject Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mean SD
DISCUSSION This is the first study to systematically assess the relationship between respiratory effort and arousal using both Pes and EMGdi during both obstructive apnea and hypopnea events. The main finding of the current study is that the range of neural drive associated with arousal is wide, even when the breaths were confined to stage 2 sleep in supine posture; moreover, using either EMGdi or Pes, neural respiratory drive was similar at the end of both apneas and hypopneas that terminated with arousal and those that did not. In addition, although the Pes and EMGdi at the end of respiratory events were usually larger than the mean of Pes or EMGdi at the middle of events, the Pes and EMGdi from some breaths during the middle of apnea or hypopnea events were larger than those at the end of respiratory events that were associated with arousal. Taken together these data argue against the concept that the magnitude of neural drive observed in apneas or hypopneas causes arousal. Critique of the Method Although the study had a comparatively small sample size, it measured respiratory effort simultaneously from both esophageal pressure and the EMGdi in over 1,600 breaths. We analyzed data from sleep stage 2 of NREM. A key reason for restricting analysis to supine N2 was to control for posture and the major known effect of sleep depth and stage on arousal propensity, and the predominance of stage 2 in sleep. The purpose of the study was to determine whether arousal is triggered by neural respiratory drive rather than to determine the difference in neural respiratory drive between sleep stages. In this study, we initially tried to record airflow using a pneumotachograph, but some patients did not tolerate this. Consequently, airflow in some subjects was recorded by pressure SLEEP, Vol. 38, No. 6, 2015
Pes Hypopnea 71% 33% 30% 42% 8% 12% 13% 20% 33% 0% 9% 18% 16% 15% 0% 17% 0% 20% 18%
OSA 17% 0% 0% 0% 0% 6% 0% 18% 8% 0% 13% 9% 10% 6% 0% 0% 20% 6% 7%
EMGdi Hypopnea OSA 40% 14% 47% 0% 60% 8% 17% 0% 19% 0% 35% 13% 25% 25% 20% 12% 37% 8% 38% 0% 9% 25% 71% 36% 38% 10% 9% 6% 31% 6% 22% 29% 60% 20% 34% 12% 18% 11%
and thermal sensors. The pneumotachograph is considered to be the most accurate method for the measurement of airflow. However, pressure and thermal sensors for the measurement of airflow have been validated, and they have become the most common method for measuring airflow in sleep medicine. Since this type of sensor can distinguish the presence or absence of airflow, we believe that the use of different methodologies for the measurement of airflow will not have significantly affected our conclusions. We did not further analyze the rate of increase of Pes during apneas because it has previously been reported to correlate well with esophageal pressure 945
Neural Respiratory Drive and Arousal—Xiao et al.
Figure 4—Esophageal pressure and diaphragm EMG during respiratory events and before respiratory events are sometimes larger than those at the end of the events, although arousal occurs only at the end of events for hypopnea (A) and apnea (B).
at the end of apnea.14–16 More importantly, Pes can be affected by airflow, lung volume, and abdominal muscle activity.9,10,12 EMGdi recorded from a single-pair esophageal electrode could be unreliable because of difficulties in positioning and in tracking diaphragm movements during breathing. However, the EMGdi recorded from a multi-pair esophageal electrode is usually considered to be relatively free from artifacts by selecting the maximal EMGdi of five pairs of electrodes. Consequently, EMGdi has been used to accurately assess neural SLEEP, Vol. 38, No. 6, 2015
respiratory drive.8,9,12,17 It has been suggested that EMG would be superior to esophageal pressure when there is change in lung volume and airflow.9,10,12 Although Younes3 described an extended time between the end of respiratory events and arousal from sleep to be as long as 15 seconds, no consensus guideline has been developed regarding an accurate estimate of the time that should elapse between the end of apnea and arousal. However, in our experience, development of arousal and resumption of airflow usually occur almost at the same 946
Neural Respiratory Drive and Arousal—Xiao et al.
hypopnea apnea
Figure 5—The mean diaphragm EMG at the beginning and during hypopneas from 4 subjects was larger than that at the end of apneas.
Figure 6—Change in neural drive is irregular and during the respiratory events it is sometimes larger than that at the end of apnea event during REM sleep. SLEEP, Vol. 38, No. 6, 2015
947
Neural Respiratory Drive and Arousal—Xiao et al.
time. Consequently, respiratory event related arousal was defined as time difference between resumption of airflow and development of arousal less than a breathing cycle. Although blood pressure and heart rate have been occasionally used to assess arousal in patients with OSA,4,18 we used conventional cortical arousal, which is defined as an abrupt shift in the EEG that lasts longer than 3 seconds.13 Variation of arousal threshold has sometimes been attributed to the influence of different sleep stages on arousal threshold,19–21 but this cannot explain our present observations derived from stage 2 sleep. A large variation in neural respiratory drive may not be explained by different recording times either, because neural respiratory drive changes little over the course of the night, as shown in this study and previous studies.22,23 Moreover, the significant difference in neural respiratory drive at the end of respiratory events between hypopneas and apneas could not be explained by different recording times because apneas and hypopneas events adjoining each other were deliberately selected.
shown that arousal index is not associated with esophageal pressure25 during CPAP treatment in patients with OSA. Third, Pes decreases following resumption of airflow,9,12 but arousal sometimes occurs after resumption of airflow rather than at the end of an apnea.3 Lastly, changes in Pes or EMGdi are irregular during REM sleep, and the Pes or EMGdi at the beginning of apnea or hypopnea events may be larger than that at the end of apnea as reported by Haba-Rubio et al.26 and demonstrated in the present study (Figure 6), but arousal does not develop at the beginning of respiratory events. In addition to the above data, it has also been observed that neural respiratory drive immediately prior to apnea events during sleep was sometimes larger than that at the end of the apnea event,27 as shown in Figure 4 of the current study. If arousal was really triggered by neural respiratory drive, patients should have not resumed sleep to generate subsequent apneic events. Our data suggest that the concept of a threshold level of neural respiratory drive cannot be the only factor that contributes to respiratory events related arousal. The concept of a threshold of esophageal pressure associated with arousal was initially described by Gleeson et al.7 However, they studied normal subjects with a small sample size and a model using hypoxia, hypercapnia, and increased airway resistance to simulate stimuli that occur in OSA patients. Moreover, they did not combine these features in a single subject as happens in patients with OSA. More importantly, their data from some subjects were actually similar to the present study (Figure 2) and show that Pes varies remarkably prior to arousal between events; for example, Pes ranged from 7.5 to 14 cm H2O for subject 8 and from 21.5 to 30 cm H2O for subject 2 in their study.7 Therefore, the data that generated the initial concept that arousal is triggered by esophageal pressure are not perfect. Kimoff et al.6 reported a similar mean transdiaphragmatic tension-time index (TTdi) at the end of apneas between different stimuli (e.g., adding oxygen or CO2), based on data obtained from patients with a narrow range of disease severity (AHI 54–79 events/h) and severe obesity (BMI 36.0–46.9 kg/m 2). A similar TTdi at the end of apnea events between subjects in the Kimoff study might be related to similar disease severity and obesity rather than similar arousal threshold because Pes correlates well with the AHI and BMI.15 It should be pointed out that similar mean values do not rule out high intra-individual variability. For example, in the present study, the mean Pes at the end of respiratory events is similar between apnea and hypopnea, whereas a wide variation exists in Pes between events within individual subjects (Figure 2). Pes varied from 13 to 124 cm H 2O at the end of apneas,16 and substantial changes in Pes within the same sleep stage and subject 23,28–29 could be an additional point to argue against the concept that arousal is triggered by neural respiratory drive. It may be worth discussing why neural drive sometimes does not increase although PCO2 may increase gradually during apnea. It is true that neural drive increases with increase of PCO2 , and therefore neural drive should increase during apnea. However, neural drive could decrease under the substantial load (e.g., upper airway collapse completely) as showed in an animal study30 to avoid peripheral muscle fatigue because of
Significance of the Findings Our results suggest that there is no fixed threshold of respiratory drive triggering arousal. If there was a threshold of neural respiratory drive responsible for arousal at the end of respiratory events, the EMGdi before arousal should be similar for each event and generation of a given neural respiratory drive should reliably trigger arousal. However, our results showed that there was big variation in either EMGdi or Pes before arousals during either apnea or hypopnea events (Figure 2). There are a significant number of arousal-related obstructive events (1 in 9 apneas, 1 in 3 hypopneas), whose neural drive during early or middle of events was already larger than that at the end of event, but arousal does not develop until at the end of apnea or hypopnea events. If arousal is triggered by neural respiratory drive, it would have occurred earlier rather than at the end of events (Figure 4). It has been generally considered that the mechanism of arousal for apnea should be the same as that for hypopnea,6,11 although the degree of airway obstruction may differ. If a specific threshold of respiratory drive was truly responsible for arousal, the EMGdi at the end of hypopneas should be the same as that at the end of apneas. However, the current study shows that EMGdi at the end of hypopnea events is significantly larger than that at the end of apnea events. Moreover, in some subjects, EMGdi over the course of hypopnea event was larger than that at the end of apnea event (Figure 5). If arousal was triggered by a threshold of neural respiratory drive, it should have developed earlier during the course of the hypopnea event in these subjects. These results are consistent with other findings that argue against the concept that arousal is triggered by neural respiratory drive. First, a wide variability in neural drive was observed between events within individual subjects based on Pes, a traditional measurement or EMGdi, a more accurate measurement of neural respiratory drive. Second, patients with OSA who receive suboptimal treatment with continuous positive airway pressure (CPAP), which might prevent obstructive apneas but not hypopneas, exhibit a higher arousal index, although their esophageal pressure swings are reduced.24 Indeed, it has been SLEEP, Vol. 38, No. 6, 2015
948
Neural Respiratory Drive and Arousal—Xiao et al.
neural inhibition. Neural inhibition under the substantial load may explain why neural drive at the end of apnea could be smaller than that at the middle of the events. In conclusion, respiratory events during sleep commonly terminate with arousal that is not related to the magnitude of neural respiratory drive.
12. Luo YM, Tang J, Jolley C, et al. Distinguishing obstructive from central sleep apnea events: diaphragm electromyogram and esophageal pressure compared. Chest 2009;135:1133–41. 13. Berry RB, Budhiraja R, Gottlieb DJ, et al.; American Academy of Sleep Medicine. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2012;8:597– 619. 14. Hamnegard CH, Polkey MI, Kyroussis D, et al. Maximum rate of change in esophageal pressure assessed from unoccluded breaths: an option where mouth occlusion pressure is impractical. Eur Respir J 1998;12:693–7. 15. Sforza E, Boudewijns A, Schnedecker B, Zamagni M, Krieger J. Role of chemosensitivity in intrathoracic pressure changes during obstructive sleep apnea. Am J Respir Crit Care Med 1996;154:1741–7. 16. Krieger J, Sforza E, Boudewijns A, Zamagni M, Petiau C. Respiratory effort during obstructive sleep apnea: role of age and sleep state. Chest 1997;112:875–84. 17. Steier J, Jolley CJ, Seymour J, et al. Sleep-disordered breathing in unilateral diaphragm paralysis or severe weakness. Eur Respir J 2008;32:1479–87. 18. Pitson DJ, Stradling JR. Autonomic markers of arousal during sleep in patients undergoing investigation for obstructive sleep apnea, their relationship to EEG arousals, respiratory events and subjective sleepiness. J Sleep Res 1998;7:53–9. 19. Ratnavadivel R, Stadler D, Windler S, et al. Upper airway function and arousability to ventilatory challenge in slow wave versus stage 2 sleep in obstructive sleep apnea. Thorax 2010;65:107–12. 20. Williams HL, Hammack JT, Daly RL, Dement WC, Lubin A. Responses to auditory stimulation, sleep loss and the EEG stages of sleep. Electroencephalogr Clin Neurophysiol 1964;16:269–79. 21. Neckelmann D, Ursin R. Sleep stages and EEG power spectrum in relation to acoustical stimulus arousal threshold in the rat. Sleep 1993;16:467–77. 22. Rees K, Spence DP, Earis JE, Calverley PM. Arousal responses from apneic events during non-rapid-eye-movement sleep. Am J Respir Crit Care Med 1995;152:1016–21. 23. Wilcox PG, Pare PD, Road JD, Fleetham JA. Respiratory muscle function during obstructive sleep apnea. Am Rev Respir Dis 1990;142:533–9. 24. Luo YM, Qiu ZH, Wu HD, et al. Neural drive during continuous positive airway pressure (cpap) and pressure relief cpap. Sleep Med 2009;10:731–8. 25. Montserrat JM, Ballester E, Olivi H, et al. Time-course of stepwise CPAP titration. Behavior of respiratory and neurological variables. Am J Respir Crit Care Med 1995;152:1854–9. 26. Haba-Rubio J, Sforza E, Weiss T, Schroder C, Krieger J. Effect of CPAP treatment on inspiratory arousal threshold during NREM sleep in OSAS. Sleep Breath 2005;9:12–9. 27. Steier J, Jolley CJ, Seymour J, et al. Increased load on the respiratory muscles in obstructive sleep apnea. Respir Physiol Neurobiol 2010;171:54–60. 28. Berry RB, Asyali MA, McNellis MI, Khoo MC. Within-night variation in respiratory effort preceding apnea termination and EEG delta power in sleep apnea. J Appl Physiol 1998;85:1434–41. 29. Loewen A, Ostrowski M, Laprairie J, et al. Determinants of ventilatory instability in obstructive sleep apnea: inherent or acquired? Sleep 2009;32:1355–65. 30. Ferguson GT. Respiratory failure due to altered central drive during inspiratory loading in rabbits. Respir Physiol 1995;99:75–87.
ACKNOWLEDGMENTS Ms. Xiao, Dr. He, and Dr. Luo contributed to study concept, design, recruitment, data acquisition and manuscript writing. Dr. Steier and Professors Moxham and Polkey contributed to study concept, design, statistical analysis, data interpretation, and manuscript writing. DISCLOSURE STATEMENT This was not an industry supported study. This study is supported by National Nature Science Foundation of China (NSFC Grant No. 81120108001). MIP’s contribution to this paper was supported by the NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield Foundation NHS Trust and Imperial College who partly fund his salary. Ms. Xiao was supported by NSFC Grant No. 8140067. The authors have indicated no financial conflicts of interest. This work was done at State Key Laboratory of Respiratory Disease, Guangzhou, China. REFERENCES
1. Roehrs T, Zorick F, Wittig R, Conway W, Roth T. Predictors of objective level of daytime sleepiness in patients with sleep-related breathing disorders. Chest 1989;95:1202–6. 2. Younes M, Ostrowski M, Atkar R, Laprairie J, Siemens A, Hanly P. Mechanisms of breathing instability in patients with obstructive sleep apnea. J Appl Physiol 2007;103:1929–41. 3. Younes M. Role of arousals in the pathogenesis of obstructive sleep apnea. Am J Respir Crit Care Med 2004;169:623–33. 4. Eckert DJ, Younes MK. Arousal from sleep: implications for obstructive sleep apnea pathogenesis and treatment. J Appl Physiol 2014;116:302–13. 5. Eckert DJ, Owens RL, Kehlmann GB, et al. Eszopiclone increases the respiratory arousal threshold and lowers the apnea/hypopnea index in obstructive sleep apnea patients with a low arousal threshold. Clinical science 2011;120:505–14. 6. Kimoff RJ, Cheong TH, Olha AE, et al. Mechanisms of apnea termination in obstructive sleep apnea. Role of chemoreceptor and mechanoreceptor stimuli. Am J Respir Crit Care Med 1994;149:707–14. 7. Gleeson K, Zwillich CW, White DP. The influence of increasing ventilatory effort on arousal from sleep. Am Rev Respir Dis 1990;142:295–300. 8. Luo YM, Moxham J. Measurement of neural respiratory drive in patients with COPD. Respir Physiol Neurobiol 2005;146:165–74. 9. Luo YM, Wu HD, Tang J, et al. Neural respiratory drive during apnoeic events in obstructive sleep apnea. Eur Respir J 2008;31:650–7. 10. Xiao SC, Lu YR, Guo HX, Qiu ZH, Luo YM. Effect of expiratory load on neural inspiratory drive. Chin Med J 2012;125:3629–34. 11. Berry RB, Gleeson K. Respiratory arousal from sleep: mechanisms and significance. Sleep 1997;20:654–75.
SLEEP, Vol. 38, No. 6, 2015
949
Neural Respiratory Drive and Arousal—Xiao et al.
SUPPLEMENTAL MATERIAL
Figure S1—Esophageal balloon-electrode catheter for recording diaphragm EMG and esophageal pressure simultaneously. Five pairs of electrodes were formed and used to record the diaphragm EMG. The catheter was positioned based on the amplitude of the diaphragm EMG recorded from five pairs of electrode. Optimal position was characterized by the largest EMG amplitude recorded from pairs 1 and 5 and the smallest EMG signal recorded from pair 3 (Luo et al.9)
SLEEP, Vol. 38, No. 6, 2015
949A
Neural Respiratory Drive and Arousal—Xiao et al.
Figure S2—EMGdi at the beginning and middle of hypopneas is larger than that at the end of apneas that are terminated by an arousal (data derived from subject 8).
SLEEP, Vol. 38, No. 6, 2015
949B
Neural Respiratory Drive and Arousal—Xiao et al.
http://dx.doi.org/10.5665/sleep.4746
NEURAL RESPIRATORY DRIVE AND AROUSAL
Neural Respiratory Drive and Arousal in Patients with Obstructive Sleep Apnea Hypopnea Si-Chang Xiao, Msc1,*; Bai-Ting He, MB1,*; Joerg Steier, PhD2,3; John Moxham, MD3; Michael I. Polkey, PhD4; Yuan-Ming Luo, PhD1 State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China; 2Lane Fox Respiratory Unit, Sleep Disorders Centre, Guy’s & St Thomas’ NHS Foundation Trust, London, UK; 3Department of Respiratory Medicine, King’s College London School of Medicine, London, UK; 4NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London, UK; *co-first authors 1
Study Objectives: It has been hypothesized that arousals after apnea and hypopnea events in patients with obstructive sleep apnea are triggered when neural respiratory drive exceeds a certain level, but this hypothesis is based on esophageal pressure data, which are dependent on flow and lung volume. We aimed to determine whether a fixed threshold of respiratory drive is responsible for arousal at the termination of apnea and hypopnea using a flow independent technique (esophageal diaphragm electromyography, EMGdi) in patients with obstructive sleep apnea. Setting: Sleep center of state Key Laboratory of Respiratory Disease. Patients: Seventeen subjects (two women, mean age 53 ± 11 years) with obstructive sleep apnea/hypopnea syndrome were studied Methods: We recorded esophageal pressure and EMGdi simultaneously during overnight full polysomnography in all the subjects. Measurements and Results: A total of 709 hypopnea events and 986 apnea events were analyzed. There was wide variation in both esophageal pressure and EMGdi at the end of both apnea and hypopnea events within a subject and stage 2 sleep. The EMGdi at the end of events that terminated with arousal was similar to those which terminated without arousal for both hypopnea events (27.6% ± 13.9%max vs 29.9% ± 15.9%max, P = ns) and apnea events (22.9% ± 11.5%max vs 22.1% ± 12.6%max, P = ns). The Pes at the end of respiratory events terminated with arousal was also similar to those terminated without arousal. There was a small but significant difference in EMGdi at the end of respiratory events between hypopnea and apnea (25.3% ± 14.2%max vs 21.7% ± 13.2%max, P < 0.05]. Conclusions: Our data do not support the concept that there is threshold of neural respiratory drive that is responsible for arousal in patients with obstructive sleep apnea. Keywords: arousal, OSA, hypopnea, diaphragm EMG, esophageal pressure Citation: Xiao SC, He BT, Steier J, Moxham J, Polkey MI, Luo YM. Neural respiratory drive and arousal in patients with obstructive sleep apnea hypopnea. SLEEP 2015;38(6):941–949.
INTRODUCTION Obstructive sleep apnea (OSA) is characterized by repeated episodes of apnea and hypopnea during sleep and major pathophysiological features of OSA are intermittent hypoxia and frequent arousals. Recurrent arousals prevent consolidated sleep and it has been shown that daytime sleepiness in patients with OSA is more closely related to arousal than to hypoxia indices.1 Recent studies have also suggested that arousal could interfere with the ability to effectively recruit the upper airway dilator muscles and may precipitate further obstructive respiratory events.2–4 Thus investigating the mechanism of arousal is important to further understand the pathophysiological changes of obstructive sleep apnea and to facilitate development of new approaches for relevant treatment options.5 Several studies have argued, based on recordings of esophageal pressure (Pes) during overnight polysomnography,6,7 that there is an arousal threshold of respiratory effort triggering arousal in patients with OSA. However, Pes is affected by changes in lung volume, particularly airflow,8–10 and this fundamental physiological property could preclude accurate
evaluation of neural respiratory drive in patients with OSA, which is characterized by change in airflow. We have previously shown that while EMGdi relates closely to Pes during apnea, this is not so once airflow resumes following an apnea9 because pressure generation declines with increase in airway flow. It remains unclear whether the stimulus leading to arousal from sleep during obstructive apneas and hypopneas is related to central respiratory output.4,11 Diaphragm electromyography (EMGdi) recorded from a multi-pair esophageal electrode can accurately assess neural respiratory drive.8–10,12 If the hypothesis that neural respiratory output causes arousal was correct, a given level of respiratory drive within a given stage of sleep and therefore sleep depth should reliably trigger arousal during either apnea or hypopnea events, and the converse should also apply—specifically that arousal should not occur unless neural respiratory drive exceeds a certain threshold. Since most patients with obstructive sleep apneahypopnea syndrome present with a mixture of apneas and hypopneas, we reasoned that the untreated sleep apnea patient provides an ideal “experiment of nature” to test this hypothesis.
Submitted for publication August, 2014 Submitted in final revised form October, 2014 Accepted for publication November, 2014 Address correspondence to: Y.M. Luo, PhD, Professor of Respiratory Medicine, State Key Laboratory of Respiratory Disease, 151 Yanjiang Road, Guangzhou 510120, China; Tel: 0086 20 3429 4087; Email: [email protected]
METHODS Seventeen subjects aged 37 to 76 years (2 females and 15 males, mean age 53 ± 11 years, BMI 26.4 ± 3.7 kg/m2 ) with OSA were recruited from patients referred to the sleep center of Guangzhou Institute of Respiratory Disease, China; their demographic data are shown in Table 1. Patients were advised to abstain from alcohol and sedative medicines ≥ 24 h prior to the study. No patient had significant coexisting conditions
SLEEP, Vol. 38, No. 6, 2015
941
Neural Respiratory Drive and Arousal—Xiao et al.
Table 1—Anthropometric and polysomnographic data. Subject Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mean SD
Age, years 55 38 57 66 44 65 40 43 57 56 76 59 37 52 62 45 51 53.1 10.9
Sex M M M F M F M M M M M M M M M M M – –
Height, m 1.61 1.86 1.71 1.53 1.66 1.47 1.65 1.73 1.70 1.70 1.57 1.68 1.75 1.67 1.60 1.60 1.75 1.66 0.09
Weight, kg 69.5 88 84 58 79 68 90 87 65 77 50.5 73 84 65 72 70 58 72.8 11.6
AHI 42.6 54.0 49.4 28.0 42.6 61.9 48.1 58.9 23.0 21.9 47.5 60.3 68.5 44.3 72.5 53.0 22.9 47.0 15.7
Sleep Efficiency 78% 90% 98% 55% 94% 73% 85% 94% 73% 74% 90% 80% 89% 77% 83% 89% 78% 82.4% 10.6%
Maximal EMGdi Recording Immediately prior to lights off, the maximal EMGdi was recorded from a series of maximal inspiratory maneuvers including maximum sniff efforts from functional residual capacity, maximal isovolumetric inspiratory contraction at FRC (Mueller maneuver), and maximal inspiration from FRC to total lung capacity. Each maneuver was performed in the supine position and repeated until 3 maximal and reproducible values were obtained. There was a minimum period of 1 min of rest between the different maneuvers. The maximum was defined as the highest level of EMGdi observed during any of these 3 maneuvers.
(such as neuromuscular disease) that were likely to affect respiratory muscle function. The study was approved by the ethics committee of The First Affiliated Hospital of Guangzhou Medical University, and all subjects gave their informed consent. Esophageal Electrode and Its Positioning The EMGdi was recorded from a balloon-electrode catheter (Yinghui Medical Equipment and Scientific Ltd, Guangzhou, China) as previously described (for further details please refer to the supplemental material, Figure S1).12 Briefly, the catheter with 10 electrodes (which formed 5 pairs) was passed through the nose and was swallowed into the esophagus. It was positioned close to the electrically active region of the diaphragm based on spontaneous EMGdi recorded from the 5 pairs of electrodes in the supine position.12 The catheter was securely taped at the nose. The EMGdi signals were amplified and band-pass filtered between 20 Hz and 1 kHz (Yinghui Medical Equipment of Scientific Ltd., Guangzhou, China). The balloon was connected to a pressure transducer (DP 15 Validyne, Northridge, CA, USA) to measure Pes.
Data Analysis Data were analyzed off-line. Arousal was defined, per convention, as an abrupt shift in the EEG lasting > 3 seconds.13 Respiratory event related arousal was defined as resumption of airflow and development of arousal at the same time (e.g., within a breathing cycle). The root mean square (RMS) of the raw signal of the EMGdi was calculated by computer using a time constant of 100 ms. The RMS reported was that from the electrode pair with the largest EMGdi amplitude for each breathing cycle. To avoid artifactual interference from the electrocardiogram, RMS was measured from the segments between QRS complexes. An obstructive apnea was defined as absence of airflow > 10 sec while there was ongoing phasic inspiratory EMGdi. An obstructive hypopnea was defined as reduction of airflow > 30% for > 10 sec associated with ≥ 3% desaturation or the event being associated with arousal.13 Obstructive apneas and hypopneas were selected for further analysis in stage 2 and REM sleep restricted to the supine position. To minimize the effect of sleep times on the arousal threshold, apneas and hypopneas events adjoining each other were selected. We arbitrarily divided each respiratory event into 3
Recording of Polysomnography, Pes, and EMGdi Conventional polysomnography including electroencephalogram (EEG) (C3-A2, C4-A1), left and right electro-oculograms (EOG), submental electromyogram (EMGchin), airflow recorded from a pneumotachograph (10 subjects) or pressure and thermal sensors (7 subjects), snoring, body position, and oxygen saturation was undertaken overnight using a Powerlab recording system (ADInstruments, Castle Hill, Australia). In addition to the conventional polysomnography, Pes and 5 pairs of EMGdi were recorded during overnight polysomnography. The sample frequency was 2 kHz for EMGdi and 200 Hz for other signals. SLEEP, Vol. 38, No. 6, 2015
BMI, kg/m2 26.8 25.4 28.7 24.8 28.7 31.5 33.1 29.1 22.5 26.6 20.5 25.9 27.4 23.3 28.1 27.3 18.9 26.4 3.7
942
Neural Respiratory Drive and Arousal—Xiao et al.
Neural Respiratory Drive at the End of Respiratory Events Terminated with or without Arousal during Stage 2 Sleep The majority of respiratory events were terminated with arousal, and in 5 subjects, all respiratory events were terminated
sections: the beginning which included the first respiratory effort without airflow, the middle which was between the first and the last obstructed breath, and the end which contained the last respiratory effort before arousal and resumption of airflow. Data are presented as mean ± SD, and a paired t-test was applied for examining statistical differences between hypopnea and apnea events. An ANOVA and a post hoc StudentNewman-Keuls test were performed to test the difference in neural respiratory drive over the respiratory events. RESULTS Variability of Esophageal Pressure and Diaphragm EMG during Stage 2 Sleep A total of 986 obstructive apneas and 709 hypopneas were analyzed when supine in sleep stage N2. The EMGdi at the end of an apnea was lower than that recorded at the end of a hypopnea events (21.7% ± 13.2%max vs 25.3% ± 14.2%max, P < 0.05; Figure 1). There was a wide variation in the level of EMGdi at the end of apneas and hypopneas within individual subjects (Figure 2). The mean coefficient of variation (CV) of the EMGdi at the end of arousal related events was 29% ± 8% for apnea and 29% ± 7% for hypopnea (Table 2). The mean value of Pes for all the subjects was similar between apnea and hypopnea events (29.0 ± 12.6 cm H2O vs 27.5 ± 12.4 cm H2O, P = ns; Table 2). However, there was substantial variation in Pes at the end of apneas and hypopneas within individual subjects (Figure 2) and the CV of Pes at the end of arousal related events was 25% ± 10% for apneas and 23% ± 9%for hypopnea (Table 2).
Figure 1—Comparison of the diaphragm EMG at the end of respiratory events (apnea and hypopnea). EMGdi at the end of the hypopnea is significantly larger than that observed during the apnea (P < 0.05). Each dot represents the mean for one subject.
Table 2—Comparison of esophageal pressure and EMGdi between hypopnea and OSA at the end of events.
Subject Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mean SD
Esophageal Pressure Hypopnea OSA Mean CV Mean CV 35.1 18% 40.8 16% 15.9 40% 17.1 45% 42.1 16% 44.5 21% 24.2 25% 33.7 29% 19.5 34% 17.5 31% 34.7 17% 36.1 19% 41.5 21% 36.3 21% 37.5 15% 39.0 23% 20.2 18% 25.4 18% 24.1 30% 27.9 17% 32.2 17% 34.4 17% 46.8 9% 47.4 8% 11.1 38% 9.0 50% 11.4 23% 12.0 32% 42.9 29% 42.0 27% 20.1 15% 18.8 19% 8.8 27% 11.7 24% 27.5 23% 29.0 25% 12.4 9% 12.6 10%
EMGdi (%max) Hypopnea OSA Mean CV Mean 40.1 25% 38.8 17.1 34% 14.3 41.7 19% 36.6 19.0 54% 13.5 14.8 28% 12.1 27.3 23% 28.5 26.3 33% 21.0 25.8 29% 16.0 18.2 25% 18.1 22.9 27% 18.4 22.3 26% 19.1 59.1 19% 56.8 15.9 30% 14.6 11.3 33% 11.7 48.4 34% 34.2 14.9 30% 8.7 5.6 22% 6.2 25.3 29% 21.68* 14.2 8% 13.2
CV 23% 39% 28% 33% 24% 28% 36% 32% 23% 34% 31% 23% 34% 41% 31% 23% 15% 29% 7%
*P < 0.05 EMGdi for hypopnea is significant higher than that for OSA. CV, coefficient of variation. SLEEP, Vol. 38, No. 6, 2015
943
Neural Respiratory Drive and Arousal—Xiao et al.
Figure 2—There is a wide variation in diaphragm EMG (A) and esophageal pressure (B) recordings at the end of apneas and hypopneas within an individual subject (data derived from subject 7).
Table 3—Esophageal pressure and diaphragm EMG at the end of the hypopnea and apnea events with and without arousal.
Subject Number 1 3 4 8 9 13 14 15 Mean SD
Pes (cmH2O) Hypopnea OSA With Without With Without 35.1 40.7 40.8 41.7 42.2 43.4 44.5 39.4 24.2 27.7 33.7 29.3 37.5 36.7 39.1 38.2 20.2 21.4 25.4 25.4 11.1 13.5 9.0 8.9 11.4 9.8 12.0 8.2 42.9 44.3 42.1 47.1 28.1 29.7 30.8 29.8 13.1 13.6 13.9 14.8
by an arousal from sleep, but a minority of hypopnea events (15.5% ± 14.2%) and apnea events (9.5% ± 11.6%) were terminated without arousal. The mean EMGdi at the end of obstructive respiratory events that terminated with arousal was similar to that terminated without arousal (22.9% ± 11.5%max vs 22.1% ± 12.6%max for apneas, P = ns; 27.6% ± 13.9%max vs 29.9% ± 15.9%max for hypopneas, P = ns; Table 3, Figure 3). Similarly, Pes at the end of obstructive respiratory events that terminated with arousal was similar to those terminated without arousal (30.8 ± 13.9 cm H2O vs 29.8 ± 14.8 cm H2O for apneas, P = ns; 28.1 ± 13.1 cm H2O vs 29.7 ± 13.6 cm H2O for hypopneas, P = ns; Table 3).
was observed, if present, at the end rather than at the middle of the apnea or hypopnea events. Changes in Pes over the course of apneas and hypopneas associated with arousal were similar to changes in EMGdi (Table 4 and Figure 4). EMGdi during sleep immediately before apnea was sometimes larger than that at the end of apnea (Figure 4). In some subjects (n = 4), EMGdi over the course of hypopneas was larger than that at the end of apneas (Figure 5 and Figure S2, supplemental material). Neural Respiratory Drive at the End of Apnea and Hypopnea Events at Different Sleep Times during Stage 2 Sleep Respiratory drive at the end of apnea and hypopnea events during the first 3 h of sleep was the same as that during the last 3 h of sleep, as assessed by Pes (28.5 ± 12.4 cm H2O vs 27.2 ± 12.2 cm H2O, P = ns) and EMGdi (21.5 ± 13.0%max vs 22.4 ± 13.3%max, P = ns).
Change of Neural Respiratory Drive over the Course of Apneas and Hypopneas Associated with Arousal Neural respiratory drive, whether assessed by Pes or EMGdi at the end of an apnea event was usually higher than that at the beginning or middle of an obstructive respiratory event, but this was not always the case (Figure 4). EMGdi during the middle of each event was higher than that at the end of the event in 12% ± 11% of apneas and 34% ± 18% of hypopneas, but arousal SLEEP, Vol. 38, No. 6, 2015
EMGdi (%max) Hypopnea OSA With Without With Without 40.1 44.6 38.8 37.6 41.7 49.3 36.6 34.8 19.0 22.4 13.5 10.8 25.8 21.8 16.0 16.6 18.2 17.5 18.1 18.1 15.9 20.9 14.7 15.1 11.3 11.1 11.7 6.3 48.4 51.6 34.2 37.5 27.6 29.9 22.9 22.1 13.9 15.9 11.5 12.6
Neural Respiratory Drive during Apnea and Hypopnea Events during REM Unlike neural respiratory drive during stage 2, neural drive appeared highly variable and did not increase gradually over 944
Neural Respiratory Drive and Arousal—Xiao et al.
Figure 3—The mean of the esophageal pressure (A) and diaphragm EMG (B) at the end of apneas that were associated with arousal from sleep are similar to those without arousal (data derived from subject 8).
the course of the apnea or hypopnea events during REM sleep. Pes and EMGdi at the middle of an obstructive respiratory event were sometimes larger than those at the end of the apnea and hypopnea event, although arousal commonly developed immediately after apnea or hypopnea (Figure 6).
Table 4—Percentage of events whose esophageal pressure or EMGdi from one of the event is larger than those at the end of the event. Subject Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Mean SD
DISCUSSION This is the first study to systematically assess the relationship between respiratory effort and arousal using both Pes and EMGdi during both obstructive apnea and hypopnea events. The main finding of the current study is that the range of neural drive associated with arousal is wide, even when the breaths were confined to stage 2 sleep in supine posture; moreover, using either EMGdi or Pes, neural respiratory drive was similar at the end of both apneas and hypopneas that terminated with arousal and those that did not. In addition, although the Pes and EMGdi at the end of respiratory events were usually larger than the mean of Pes or EMGdi at the middle of events, the Pes and EMGdi from some breaths during the middle of apnea or hypopnea events were larger than those at the end of respiratory events that were associated with arousal. Taken together these data argue against the concept that the magnitude of neural drive observed in apneas or hypopneas causes arousal. Critique of the Method Although the study had a comparatively small sample size, it measured respiratory effort simultaneously from both esophageal pressure and the EMGdi in over 1,600 breaths. We analyzed data from sleep stage 2 of NREM. A key reason for restricting analysis to supine N2 was to control for posture and the major known effect of sleep depth and stage on arousal propensity, and the predominance of stage 2 in sleep. The purpose of the study was to determine whether arousal is triggered by neural respiratory drive rather than to determine the difference in neural respiratory drive between sleep stages. In this study, we initially tried to record airflow using a pneumotachograph, but some patients did not tolerate this. Consequently, airflow in some subjects was recorded by pressure SLEEP, Vol. 38, No. 6, 2015
Pes Hypopnea 71% 33% 30% 42% 8% 12% 13% 20% 33% 0% 9% 18% 16% 15% 0% 17% 0% 20% 18%
OSA 17% 0% 0% 0% 0% 6% 0% 18% 8% 0% 13% 9% 10% 6% 0% 0% 20% 6% 7%
EMGdi Hypopnea OSA 40% 14% 47% 0% 60% 8% 17% 0% 19% 0% 35% 13% 25% 25% 20% 12% 37% 8% 38% 0% 9% 25% 71% 36% 38% 10% 9% 6% 31% 6% 22% 29% 60% 20% 34% 12% 18% 11%
and thermal sensors. The pneumotachograph is considered to be the most accurate method for the measurement of airflow. However, pressure and thermal sensors for the measurement of airflow have been validated, and they have become the most common method for measuring airflow in sleep medicine. Since this type of sensor can distinguish the presence or absence of airflow, we believe that the use of different methodologies for the measurement of airflow will not have significantly affected our conclusions. We did not further analyze the rate of increase of Pes during apneas because it has previously been reported to correlate well with esophageal pressure 945
Neural Respiratory Drive and Arousal—Xiao et al.
Figure 4—Esophageal pressure and diaphragm EMG during respiratory events and before respiratory events are sometimes larger than those at the end of the events, although arousal occurs only at the end of events for hypopnea (A) and apnea (B).
at the end of apnea.14–16 More importantly, Pes can be affected by airflow, lung volume, and abdominal muscle activity.9,10,12 EMGdi recorded from a single-pair esophageal electrode could be unreliable because of difficulties in positioning and in tracking diaphragm movements during breathing. However, the EMGdi recorded from a multi-pair esophageal electrode is usually considered to be relatively free from artifacts by selecting the maximal EMGdi of five pairs of electrodes. Consequently, EMGdi has been used to accurately assess neural SLEEP, Vol. 38, No. 6, 2015
respiratory drive.8,9,12,17 It has been suggested that EMG would be superior to esophageal pressure when there is change in lung volume and airflow.9,10,12 Although Younes3 described an extended time between the end of respiratory events and arousal from sleep to be as long as 15 seconds, no consensus guideline has been developed regarding an accurate estimate of the time that should elapse between the end of apnea and arousal. However, in our experience, development of arousal and resumption of airflow usually occur almost at the same 946
Neural Respiratory Drive and Arousal—Xiao et al.
hypopnea apnea
Figure 5—The mean diaphragm EMG at the beginning and during hypopneas from 4 subjects was larger than that at the end of apneas.
Figure 6—Change in neural drive is irregular and during the respiratory events it is sometimes larger than that at the end of apnea event during REM sleep. SLEEP, Vol. 38, No. 6, 2015
947
Neural Respiratory Drive and Arousal—Xiao et al.
time. Consequently, respiratory event related arousal was defined as time difference between resumption of airflow and development of arousal less than a breathing cycle. Although blood pressure and heart rate have been occasionally used to assess arousal in patients with OSA,4,18 we used conventional cortical arousal, which is defined as an abrupt shift in the EEG that lasts longer than 3 seconds.13 Variation of arousal threshold has sometimes been attributed to the influence of different sleep stages on arousal threshold,19–21 but this cannot explain our present observations derived from stage 2 sleep. A large variation in neural respiratory drive may not be explained by different recording times either, because neural respiratory drive changes little over the course of the night, as shown in this study and previous studies.22,23 Moreover, the significant difference in neural respiratory drive at the end of respiratory events between hypopneas and apneas could not be explained by different recording times because apneas and hypopneas events adjoining each other were deliberately selected.
shown that arousal index is not associated with esophageal pressure25 during CPAP treatment in patients with OSA. Third, Pes decreases following resumption of airflow,9,12 but arousal sometimes occurs after resumption of airflow rather than at the end of an apnea.3 Lastly, changes in Pes or EMGdi are irregular during REM sleep, and the Pes or EMGdi at the beginning of apnea or hypopnea events may be larger than that at the end of apnea as reported by Haba-Rubio et al.26 and demonstrated in the present study (Figure 6), but arousal does not develop at the beginning of respiratory events. In addition to the above data, it has also been observed that neural respiratory drive immediately prior to apnea events during sleep was sometimes larger than that at the end of the apnea event,27 as shown in Figure 4 of the current study. If arousal was really triggered by neural respiratory drive, patients should have not resumed sleep to generate subsequent apneic events. Our data suggest that the concept of a threshold level of neural respiratory drive cannot be the only factor that contributes to respiratory events related arousal. The concept of a threshold of esophageal pressure associated with arousal was initially described by Gleeson et al.7 However, they studied normal subjects with a small sample size and a model using hypoxia, hypercapnia, and increased airway resistance to simulate stimuli that occur in OSA patients. Moreover, they did not combine these features in a single subject as happens in patients with OSA. More importantly, their data from some subjects were actually similar to the present study (Figure 2) and show that Pes varies remarkably prior to arousal between events; for example, Pes ranged from 7.5 to 14 cm H2O for subject 8 and from 21.5 to 30 cm H2O for subject 2 in their study.7 Therefore, the data that generated the initial concept that arousal is triggered by esophageal pressure are not perfect. Kimoff et al.6 reported a similar mean transdiaphragmatic tension-time index (TTdi) at the end of apneas between different stimuli (e.g., adding oxygen or CO2), based on data obtained from patients with a narrow range of disease severity (AHI 54–79 events/h) and severe obesity (BMI 36.0–46.9 kg/m 2). A similar TTdi at the end of apnea events between subjects in the Kimoff study might be related to similar disease severity and obesity rather than similar arousal threshold because Pes correlates well with the AHI and BMI.15 It should be pointed out that similar mean values do not rule out high intra-individual variability. For example, in the present study, the mean Pes at the end of respiratory events is similar between apnea and hypopnea, whereas a wide variation exists in Pes between events within individual subjects (Figure 2). Pes varied from 13 to 124 cm H 2O at the end of apneas,16 and substantial changes in Pes within the same sleep stage and subject 23,28–29 could be an additional point to argue against the concept that arousal is triggered by neural respiratory drive. It may be worth discussing why neural drive sometimes does not increase although PCO2 may increase gradually during apnea. It is true that neural drive increases with increase of PCO2 , and therefore neural drive should increase during apnea. However, neural drive could decrease under the substantial load (e.g., upper airway collapse completely) as showed in an animal study30 to avoid peripheral muscle fatigue because of
Significance of the Findings Our results suggest that there is no fixed threshold of respiratory drive triggering arousal. If there was a threshold of neural respiratory drive responsible for arousal at the end of respiratory events, the EMGdi before arousal should be similar for each event and generation of a given neural respiratory drive should reliably trigger arousal. However, our results showed that there was big variation in either EMGdi or Pes before arousals during either apnea or hypopnea events (Figure 2). There are a significant number of arousal-related obstructive events (1 in 9 apneas, 1 in 3 hypopneas), whose neural drive during early or middle of events was already larger than that at the end of event, but arousal does not develop until at the end of apnea or hypopnea events. If arousal is triggered by neural respiratory drive, it would have occurred earlier rather than at the end of events (Figure 4). It has been generally considered that the mechanism of arousal for apnea should be the same as that for hypopnea,6,11 although the degree of airway obstruction may differ. If a specific threshold of respiratory drive was truly responsible for arousal, the EMGdi at the end of hypopneas should be the same as that at the end of apneas. However, the current study shows that EMGdi at the end of hypopnea events is significantly larger than that at the end of apnea events. Moreover, in some subjects, EMGdi over the course of hypopnea event was larger than that at the end of apnea event (Figure 5). If arousal was triggered by a threshold of neural respiratory drive, it should have developed earlier during the course of the hypopnea event in these subjects. These results are consistent with other findings that argue against the concept that arousal is triggered by neural respiratory drive. First, a wide variability in neural drive was observed between events within individual subjects based on Pes, a traditional measurement or EMGdi, a more accurate measurement of neural respiratory drive. Second, patients with OSA who receive suboptimal treatment with continuous positive airway pressure (CPAP), which might prevent obstructive apneas but not hypopneas, exhibit a higher arousal index, although their esophageal pressure swings are reduced.24 Indeed, it has been SLEEP, Vol. 38, No. 6, 2015
948
Neural Respiratory Drive and Arousal—Xiao et al.
neural inhibition. Neural inhibition under the substantial load may explain why neural drive at the end of apnea could be smaller than that at the middle of the events. In conclusion, respiratory events during sleep commonly terminate with arousal that is not related to the magnitude of neural respiratory drive.
12. Luo YM, Tang J, Jolley C, et al. Distinguishing obstructive from central sleep apnea events: diaphragm electromyogram and esophageal pressure compared. Chest 2009;135:1133–41. 13. Berry RB, Budhiraja R, Gottlieb DJ, et al.; American Academy of Sleep Medicine. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2012;8:597– 619. 14. Hamnegard CH, Polkey MI, Kyroussis D, et al. Maximum rate of change in esophageal pressure assessed from unoccluded breaths: an option where mouth occlusion pressure is impractical. Eur Respir J 1998;12:693–7. 15. Sforza E, Boudewijns A, Schnedecker B, Zamagni M, Krieger J. Role of chemosensitivity in intrathoracic pressure changes during obstructive sleep apnea. Am J Respir Crit Care Med 1996;154:1741–7. 16. Krieger J, Sforza E, Boudewijns A, Zamagni M, Petiau C. Respiratory effort during obstructive sleep apnea: role of age and sleep state. Chest 1997;112:875–84. 17. Steier J, Jolley CJ, Seymour J, et al. Sleep-disordered breathing in unilateral diaphragm paralysis or severe weakness. Eur Respir J 2008;32:1479–87. 18. Pitson DJ, Stradling JR. Autonomic markers of arousal during sleep in patients undergoing investigation for obstructive sleep apnea, their relationship to EEG arousals, respiratory events and subjective sleepiness. J Sleep Res 1998;7:53–9. 19. Ratnavadivel R, Stadler D, Windler S, et al. Upper airway function and arousability to ventilatory challenge in slow wave versus stage 2 sleep in obstructive sleep apnea. Thorax 2010;65:107–12. 20. Williams HL, Hammack JT, Daly RL, Dement WC, Lubin A. Responses to auditory stimulation, sleep loss and the EEG stages of sleep. Electroencephalogr Clin Neurophysiol 1964;16:269–79. 21. Neckelmann D, Ursin R. Sleep stages and EEG power spectrum in relation to acoustical stimulus arousal threshold in the rat. Sleep 1993;16:467–77. 22. Rees K, Spence DP, Earis JE, Calverley PM. Arousal responses from apneic events during non-rapid-eye-movement sleep. Am J Respir Crit Care Med 1995;152:1016–21. 23. Wilcox PG, Pare PD, Road JD, Fleetham JA. Respiratory muscle function during obstructive sleep apnea. Am Rev Respir Dis 1990;142:533–9. 24. Luo YM, Qiu ZH, Wu HD, et al. Neural drive during continuous positive airway pressure (cpap) and pressure relief cpap. Sleep Med 2009;10:731–8. 25. Montserrat JM, Ballester E, Olivi H, et al. Time-course of stepwise CPAP titration. Behavior of respiratory and neurological variables. Am J Respir Crit Care Med 1995;152:1854–9. 26. Haba-Rubio J, Sforza E, Weiss T, Schroder C, Krieger J. Effect of CPAP treatment on inspiratory arousal threshold during NREM sleep in OSAS. Sleep Breath 2005;9:12–9. 27. Steier J, Jolley CJ, Seymour J, et al. Increased load on the respiratory muscles in obstructive sleep apnea. Respir Physiol Neurobiol 2010;171:54–60. 28. Berry RB, Asyali MA, McNellis MI, Khoo MC. Within-night variation in respiratory effort preceding apnea termination and EEG delta power in sleep apnea. J Appl Physiol 1998;85:1434–41. 29. Loewen A, Ostrowski M, Laprairie J, et al. Determinants of ventilatory instability in obstructive sleep apnea: inherent or acquired? Sleep 2009;32:1355–65. 30. Ferguson GT. Respiratory failure due to altered central drive during inspiratory loading in rabbits. Respir Physiol 1995;99:75–87.
ACKNOWLEDGMENTS Ms. Xiao, Dr. He, and Dr. Luo contributed to study concept, design, recruitment, data acquisition and manuscript writing. Dr. Steier and Professors Moxham and Polkey contributed to study concept, design, statistical analysis, data interpretation, and manuscript writing. DISCLOSURE STATEMENT This was not an industry supported study. This study is supported by National Nature Science Foundation of China (NSFC Grant No. 81120108001). MIP’s contribution to this paper was supported by the NIHR Respiratory Biomedical Research Unit at the Royal Brompton and Harefield Foundation NHS Trust and Imperial College who partly fund his salary. Ms. Xiao was supported by NSFC Grant No. 8140067. The authors have indicated no financial conflicts of interest. This work was done at State Key Laboratory of Respiratory Disease, Guangzhou, China. REFERENCES
1. Roehrs T, Zorick F, Wittig R, Conway W, Roth T. Predictors of objective level of daytime sleepiness in patients with sleep-related breathing disorders. Chest 1989;95:1202–6. 2. Younes M, Ostrowski M, Atkar R, Laprairie J, Siemens A, Hanly P. Mechanisms of breathing instability in patients with obstructive sleep apnea. J Appl Physiol 2007;103:1929–41. 3. Younes M. Role of arousals in the pathogenesis of obstructive sleep apnea. Am J Respir Crit Care Med 2004;169:623–33. 4. Eckert DJ, Younes MK. Arousal from sleep: implications for obstructive sleep apnea pathogenesis and treatment. J Appl Physiol 2014;116:302–13. 5. Eckert DJ, Owens RL, Kehlmann GB, et al. Eszopiclone increases the respiratory arousal threshold and lowers the apnea/hypopnea index in obstructive sleep apnea patients with a low arousal threshold. Clinical science 2011;120:505–14. 6. Kimoff RJ, Cheong TH, Olha AE, et al. Mechanisms of apnea termination in obstructive sleep apnea. Role of chemoreceptor and mechanoreceptor stimuli. Am J Respir Crit Care Med 1994;149:707–14. 7. Gleeson K, Zwillich CW, White DP. The influence of increasing ventilatory effort on arousal from sleep. Am Rev Respir Dis 1990;142:295–300. 8. Luo YM, Moxham J. Measurement of neural respiratory drive in patients with COPD. Respir Physiol Neurobiol 2005;146:165–74. 9. Luo YM, Wu HD, Tang J, et al. Neural respiratory drive during apnoeic events in obstructive sleep apnea. Eur Respir J 2008;31:650–7. 10. Xiao SC, Lu YR, Guo HX, Qiu ZH, Luo YM. Effect of expiratory load on neural inspiratory drive. Chin Med J 2012;125:3629–34. 11. Berry RB, Gleeson K. Respiratory arousal from sleep: mechanisms and significance. Sleep 1997;20:654–75.
SLEEP, Vol. 38, No. 6, 2015
949
Neural Respiratory Drive and Arousal—Xiao et al.
SUPPLEMENTAL MATERIAL
Figure S1—Esophageal balloon-electrode catheter for recording diaphragm EMG and esophageal pressure simultaneously. Five pairs of electrodes were formed and used to record the diaphragm EMG. The catheter was positioned based on the amplitude of the diaphragm EMG recorded from five pairs of electrode. Optimal position was characterized by the largest EMG amplitude recorded from pairs 1 and 5 and the smallest EMG signal recorded from pair 3 (Luo et al.9)
SLEEP, Vol. 38, No. 6, 2015
949A
Neural Respiratory Drive and Arousal—Xiao et al.
Figure S2—EMGdi at the beginning and middle of hypopneas is larger than that at the end of apneas that are terminated by an arousal (data derived from subject 8).
SLEEP, Vol. 38, No. 6, 2015
949B
Neural Respiratory Drive and Arousal—Xiao et al.
