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ARTICLE

Temporal Relationship Between Night-Time Gastroesophageal Reflux Events and Arousals From Sleep

Shepherd, Kelly BSc (Hons), PhD, MD1,2; Ockelford, James BSc (Hons)1,2; Ganasan, Vijeyadezmi BSc (Hons), MD1,2; Holloway, Richard BSc (Med), MBBS, MD, FRACP, AGAF3; Hillman, David MBBS, FANZCA1,2; Eastwood, Peter BSc, PhD1,2

Author Information
The American Journal of Gastroenterology: May 2020 - Volume 115 - Issue 5 - p 697-705
doi: 10.14309/ajg.0000000000000627

Abstract

INTRODUCTION

Night-time gastroesophageal reflux (nGER) symptoms are believed to interrupt sleep and cause daytime sleepiness and fatigue (1–5). Treatment of GER with proton pump inhibitor therapy improves subjective sleep quality, suggesting that night-time reflux events are directly influencing sleep quality (6,7). Although it is generally accepted that nGER events occur during brief arousals or more prolonged awakenings from sleep, rather than during stable sleep itself (8–12), the precise temporal relationship between nGER events and arousals remains unclear. Specifically, it remains unknown whether nGER events precipitate arousals and awakenings or whether, conversely, arousals and awakenings are required for or precipitate nGER events. There are 3 possible scenarios which could underpin these relationships: (i) a reflux event occurs during sleep, provoking arousals/awakenings (a type 1 event); (ii) a reflux event occurs during arousal/awakening from sleep (a type 2 event); and (iii) sleep is disrupted by the development of heartburn minutes after the onset of a reflux event where there has been a failure of the esophageal acid clearance mechanism (a type 3 event) (13). The latter circumstance may be particularly problematic because such an event can result in a markedly prolonged acid clearance time (ACT) and substantial damage to the esophageal mucosa.

Several studies have attempted to define the relationships between sleep, arousal, and GER events using wrist-worn actigraphy devices to estimate sleep and wake patterns (12,14–18). However, such devices cannot determine the different stages of sleep and have a tendency to underestimate the amount of wakefulness after sleep onset (19–23). Although useful for assessing overall sleep/wake patterns, they cannot precisely determine the temporal relationship between the changes in sleep state and nGER events. The most precise method of assessing the timing and occurrence of arousals and awakenings is with polysomnography (PSG), which involves the recording of electroencephalogram (EEG), electrooculogram, and electromyogram during sleep (24). Based on characteristic EEG, electromyogram, and electrooculogram patterns, PSG can be used to classify sleep into its specific stages and accurately determine the presence and timing of arousals and awakenings. Such technology has not previously been used to examine the temporal relationships between nGER events and changes in sleep state, an assessment that requires the precision that it offers. To address this deficiency, the aim of this study was to investigate the relationships between PSG-defined arousals and awakenings from sleep and nGER events.

METHODS

Subjects

Individuals who had undergone a gastroscopy for investigation of symptomatic GER disease within the previous 12 months were contacted by phone and invited to participate in the study. Participants were 18–70 years of age and had a range of severities of reflux esophagitis (none to severe based on the Los Angeles Classification System of gastroesophageal reflux disease [LA grade] [25]). Gastroscopy was performed after 7 days off acid-suppressing medication. Individuals were excluded if they were taking over-the-counter or prescription medications for GER that they were not willing to stop during the study (defined below), had a chronic medical condition, had any gastrointestinal conditions that could affect the esophageal function or acid secretion, or had previous surgery on the stomach and/or esophagus.

Protocol

Participants attended the Respiratory Sleep Disorders Clinic at Sir Charles Gairdner Hospital in the morning for insertion of a 24-hour esophageal pH-impedance catheter after which they left the hospital to carry out their usual daily activities. They returned to the clinic in the evening and were fed a standardized meal. Additional information regarding the protocol is available as Supplementary Digital Content 1 (http://links.lww.com/AJG/B504).

The study was approved by the Human Research Ethics Committee (May 17, 2012) of Sir Charles Gairdner Hospital, and written informed consent was obtained from each patient before their participation. This trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000458831).

Specific techniques

Polysomnography.

In-laboratory PSG was conducted according to the American Academy of Sleep Medicine recommendations (26) (Grael, Compumedics, Melbourne, Australia). The pH signal from the catheter was input into the PSG software in real-time to enable precise synchronization of the reflux events with arousals, awakenings, movements, and/or respiratory events.

Classification of sleep stage, arousals, and respiratory events were performed according to the standard criteria (27). Sleep efficiency, wake time after sleep onset, arousal index (ArI), and awakening index (AwI) were used as quantitative measures of sleep quality. An arousal was an increase in EEG frequency that lasted from 3 to 15 seconds and an awakening was a shift in EEG frequency lasting for >15 seconds. Additional information is available in Supplementary Digital Content 1 (http://links.lww.com/AJG/B504).

Esophageal pH/impedance monitoring.

Participants were required to cease all acid-suppression medications 7 days before the study and antacid medications 24 hours before the study. Before insertion of the pH/impedance catheter, the location of the lower esophageal sphincter was identified manometrically (28). Esophageal pH/impedance monitoring was then conducted using a pH/impedance catheter (VersaFlex pH-Z Catheters; Sierra Scientific, Los Angeles, CA), positioned with the pH sensor 5 cm above the proximal border of the lower esophageal sphincter (see online supplement for additional information Supplementary Digital Content 1, http://links.lww.com/AJG/B504). Measurements included the following: ACT; longest event, number of long events (>5 minutes in duration), total number of events, bolus exposure time (BET), and proportion of events that migrated to the proximal esophagus.

Measurements of pH were used to classify the GER events as acidic (pH < 4), weakly acidic (pH between 4 and 7), or nonacidic (pH does not drop below 7). For analysis purposes, weakly acidic and nonacidic events were combined. The change in pH was used to determine ACT (proportion of time with pH < 4 and to determine the relationship between PSG-based measurements of sleep and each reflux event. The impedance sensors were used in conjunction with the pH sensor to determine the length of GER events, BET, and number of distal and proximal reflux events. These variables were determined for the 24-hour recording period and the wake and sleep periods.

Questionnaires.

The GER Questionnaire was used to define frequency of daytime and night-time symptoms of GER (29,30). The term GER symptoms refers to the symptoms experienced at any time during the day or night, whereas night-time GER (nGER) symptoms specifically refers to the symptoms which woke the patient from sleep (31) (See additional information, Supplementary Digital Content 1, http://links.lww.com/AJG/B504).

To assess whether by negatively affecting sleep quality nGER had a detrimental impact on the degree of subjective daytime sleepiness, participants completed the Epworth Sleepiness Scale (ESS) (32).

Data analysis.

The recording period was divided into sleep and wake periods. The sleep period was defined as the time between PSG-defined sleep onset and PSG-defined waking in the morning. The wake period was calculated as the time between insertion of the pH-impedance catheter in the morning of the study and its removal the following morning minus the overall sleep period.

Participants were grouped into those who had ≥1 nGER event during the sleep period (nGER) and those who had no nGER events (no nGER). An apnea–hypopnea index (AHI) cutoff of 5 events per hour was used to define the presence (≥5 events/hr) or absence (<5 events/hr) of obstructive sleep apnea (OSA) (24,33).

All nGER events were analyzed for their temporal relationship to a PSG-defined arousal, awakening, movement, and/or obstructive respiratory event. The sleep stage in which each nGER event occurred was defined by the sleep stage of the 30 seconds epoch in which the nGER event began.

Statistical analysis.

The results are presented as mean ± SD. Statistical analyses were performed using SigmaStat (SysStat Software, San Jose, CA). Proportions of each group reporting GER symptoms or medications were compared using the χ2 tests or Fisher Exact tests. Differences between groups were compared using the unpaired t tests or Mann-Whitney rank-sum tests when data were not normally distributed. A P-value of 0.05 was used to indicate statistical significance.

RESULTS

Subject characteristics

Thirty-three individuals consented to participate in the study. Five withdrew because of the inability to tolerate the esophageal catheter. Data from a further 2 were excluded because of the failure of the pH-recording device, and data from one individual were excluded because of them taking an anxiolytic before the study (which may have affected normal sleep patterns). Therefore, data from 25 individuals were analyzed.

Those who completed the protocol were primarily men (64%) with mean age 46 ± 15 years with mean body mass index (BMI) 28 ± 5 kg/m2. Of those who completed the protocol were 9 individuals with a normal endoscopy; 2 with minor reflux changes to the gastroesophageal junction, however no definitive esophagitis; 11 patients with mild esophagitis (LA grade A–B); and 2 patients with Barrett's esophagus. The mean (SD) total acid contact time in the cohort overall was 7.9% (7.7%) with 15 of the 25 subjects having an abnormal exposure time (>4.2% (34)).

nGER vs no nGER

Of the 25 subjects who completed the protocol, 16 had at least 1 nGER event with an average of 4.9 ± 4.7 events per person (range 1–18). When comparing those with nGER episodes with those without there were no differences with regard to gender, age, BMI, GER symptoms, or prevalence of esophagitis (Table 1). Similarly, there were no differences in any sleep-related measure, including daytime sleepiness (ESS); PSG-determined sleep duration or efficiency, sleep stages, arousals, awakenings or AHI between these 2 groups (Table 2).

Table 1
Table 1:
Subject characteristics
Table 2
Table 2:
Subjective and polysomnographically defined measurements of sleep

Measurements reflecting the severity of GER are summarized in Table 3. As expected, because the 2 groups were defined on the basis of events that occurred during sleep (i.e., nGER vs no nGER), the nGER group had significantly higher ACT, BET, and number of GER events during sleep. However, these differences were not reflected in the total recording period or the wake period, although there was a trend for the nGER group to have a greater number of GER events than the no nGER group. There was no difference in the number of long events and longest event between the groups.

Table 3
Table 3:
Esophageal pH-defined measurements of reflux

OSA vs no OSA

Of the 25 subjects who completed the protocol, 16 had OSA, as defined by an AHI ≥ 5. The OSA group was significantly older and more obese than the group without OSA and had a greater proportion of individuals reporting any nGER symptoms, although there was no difference in the prevalence of esophagitis between the 2 groups (Table 1). There was no difference in daytime sleepiness (ESS) between the groups (Table 2). As expected, because the 2 groups were defined on the basis of AHI, the AwI, ArI, AHI, and proportion of N1 sleep were all significantly higher, and the proportion of N2 sleep was significantly lower in the OSA group.

Comparisons of measures of GER severity between those with and without OSA are summarized in Table 3. Most of the nGER events occurred in participants with OSA (69/76). During the sleep period BET, the number of GER events and the number of acidic GER events were all significantly increased in the OSA group, with a trend for higher ACT in the OSA group (P = 0.06). Similar differences were observed during the wake period, where ACT, BET, number of GER events, and number of acidic GER events were significantly higher in the OSA group. These differences were also apparent when considering the total recording period. Furthermore, during the total recording period, the proportion of distal nGER events that migrated proximally was increased in the OSA group. There was no difference in the number of long events and longest event between the groups.

Pattern of occurrence of nGER events

A total of 76 nGER events were recorded during sleep across the 16 subjects (mean 4.9 events/subject, Table 3). Most of the events (n = 58, 76%) were classified as acidic, with the balance nonacidic. Forty events (53%) were associated with body movement in the previous 30 seconds. Five (7%) nGER events had a respiratory event (4 hypopneas and 1 central apnea) within the preceding 30 seconds.

In both the individuals with OSA and the group as a whole, most of the nGER events (62/76, 82%) were initiated during an epoch classified as wake (i.e., during an awakening). Regarding the timing of nGER events in relation to awakenings and arousal, most of the nGER events had an awakening or arousal before the nGER onset—21/76 within the previous 30 seconds and 73/76 in the previous 5 minutes. Fewer nGER events were followed by an awakening or arousal—8/76 within the subsequent 30 seconds after nGER onset and 15/76 in the following 5 minutes (Figure 1).

Figure 1
Figure 1:
Number of nGER events associated with awakenings from sleep (>seconds in duration, solid black shading) and arousal from sleep (3–15 seconds in duration, gray shading). The x axis represents the time relative to nGER onset that arousal/awakening occurred. nGER, night-time gastroesophageal reflux.

Thirteen events (17%) occurred during an epoch classified as sleep: 6 (8%) occurred during N1 sleep, 2 (3%) during N2 sleep, and 5 (7%) during rapid eye movement (REM) sleep. No events occurred during N3 sleep. The sleep stage of 1 nGER event could not be determined because of the PSG signal artefact throughout the epoch. Five of the 13 events that occurred during an epoch of sleep had an arousal/awakening within the preceding 30 seconds of nGER onset and an additional 4 events had an arousal/awakening within the preceding 1-minute of nGER onset (Figure 1), with the remaining 4 having no preceding arousal.

Nocturnal GER events were classified according to the scenarios proposed by Dent et al. (13). As noted above, 63 nGER events occurred during an epoch of wake. Fifty-seven (75%) of these had their onset in association with an arousal or awakening from sleep and were cleared during the arousal/awakening (type 2 event, Figure 2). In 4 of the nGER events, which occurred during stage wake, the individual fell asleep before the event had cleared (type 3 event, Figure 4). Thirteen events (17%) occurred during an epoch of sleep; however, arousal/awakening was only associated with the clearance of 6 events (Figure 3), with 7/13 cleared without an arousal from sleep. In other words, although these 13 events occurred during an epoch of sleep, only 6 fit the criteria for a type 1 event, as suggested by Dent et al. (13).

Figure 2
Figure 2:
nGER event occurs during an arousal or awakening and is cleared before the individual resumes sleep (Dent et al. (13) type 2 event). Dashed line represents pH = 4; the nGER event begins when the pH drops below this level and ends when it returns to above this level. The epoch on the top panel is the 30 seconds period during which the onset of nGER event occurs. Hypnogram above upper pane and below lower pane represents the sleep stages which occurred during this section of recording (white—wake; black—sleep). Upper panel 30 seconds; lower panel 5 min. EEG, electroencephalogram; EMG, electromyogram; nGER, night-time gastroesophageal reflux.
Figure 3
Figure 3:
nGER event (onset marked with arrow) occurs during a period of stable sleep cleared during an awakening/arousal from sleep (Dent et al. (13) type 1 event). Dashed line represents pH = 4; the nGER event begins when the pH drops below this level and ends when it returns to above this level. The epoch on the top panel is the 30-second period during which the onset of nGER event occurs. Hypnogram above upper pane and below lower pane represents the sleep stages which occurred during this section of recording (white—wake; black—sleep). Upper panel 30 seconds; lower panel 1 hour. EEG, electroencephalogram; EMG, electromyogram; nGER, night-time gastroesophageal reflux.
Figure 4
Figure 4:
nGER event occurs during a period of wakefulness. The patient then falls asleep before the event can be cleared, resulting in a prolonged esophageal acid clearance time of approximately 32 minutes. The event is only cleared when the patient next arouses from sleep (Dent et al. (13) type 3 event). Dashed line represents pH = 4; the nGER event begins when the pH drops below this level and ends when it returns to above this level. The epoch on the top panel is the 30-second period during which the onset of nGER event occurs. Hypnogram above upper pane and below lower pane represents the sleep stages which occurred during this section of recording (white—wake; black—sleep). Upper panel 30 seconds; lower panel 1 hour. EEG, electroencephalogram; EMG, electromyogram; nGER, night-time gastroesophageal reflux.

DISCUSSION

The primary aim of this study was to investigate the relationship between polysomnographically determined arousals/awakenings and nGER events. The main findings are that (i) most of the nGER events occur during the periods of wakefulness after sleep onset and (ii) arousal was much more likely precede than follow nGER events, suggesting that nGER is precipitated by arousal from sleep. Additional findings were that there was no difference in subjective or objective sleep quality between individuals with and without nGER episodes and that individuals with OSA had more severe GER during the wake period and more severe nGER during the sleep periods than those without OSA.

These findings support what is widely accepted in the literature that most nGER events occur during wakeful periods after sleep onset or during brief arousal from sleep (8–12); however, this is one of the few studies to use the gold-standard, in-laboratory PSG to show this (3,10,35). Several previous studies (12,14,16,17,36) have claimed that the relationship between sleep (wake vs sleep), arousal and nGER events can be adequately determined by using actigraphy devices that rely on the detection of movement to score wake and sleep (23). However, although this technique may be useful in the assessment of overall sleep-wake patterns, it is limited in its ability to provide precise information regarding the timing of sleep/wake transitions which are essential in defining their temporal relationship to the nGER episodes. Furthermore, actigraphy is unable to provide any information on the stage of sleep.

The current study found that arousals generally precede nGER events, rather than vice versa, suggesting that it is awakening from sleep which precipitates or facilitates nGER events, rather than nGER events causing arousal. The mechanism by which arousal facilitates nGER may be via an increase in transient lower esophageal sphincter relaxation (TLESR), the main mechanism by which GER events occur in both individuals with and without GER disease (9,37). These have been shown to occur mainly during the periods of wakefulness (9, 37, 38) and have also been shown to be frequently preceded by arousal from sleep (38).

The relationships between nGER timing and occurrence of obstructive respiratory events (hypopneas and apneas) are complex. It has previously been shown that during obstructive events, the mechanical barrier to nGER events increases because diaphragmatic tension increases proportionally with the magnitude of respiratory effort (38). The associated increase in barrier pressure occurs notwithstanding the generation of a more negative intrathoracic pressure during inspiratory efforts to overcome the upper airway obstruction. Moreover, the nGER events occur far less frequently than obstructive events, as our data demonstrate. These observations are consistent with the notion that nGER events and obstructive respiratory events are not directly related and that arousal/awakening seems to be a crucial intermediary event. Notably, ESS was similar in the nGER and no nGER groups, suggesting that nGER did not have a detrimental effect on sleep quality, again consistent with the notion that nGER was not a cause of arousal from sleep, but rather a consequence of such arousals.

Dent et al. (13) suggested 3 patterns of nGER which are likely to underlie most events: type 1, where nGER onset occurs during sleep and clears shortly afterward with arousal from sleep; type 2, where nGER onset and clearance occur during arousal/awakening from sleep; and type 3, where nGER onset occurs during wakefulness but the individual falls asleep before the event being cleared, leading to prolonged ACT. In the present study, the overwhelming majority of nGER episodes (57/76 events) occurred and were cleared during awakenings or arousals from sleep, corresponding with type 2 nGER events (13). In only 4 of the 62 events that occurred during wakefulness did the subject return to sleep before the event was cleared. Although such events increase the risk of prolonged esophageal acidification, our study indicates that such type 3 events are relatively uncommon. Finally, although 13 of the 76 nGER events were initiated during an epoch of sleep, only 6 of these were cleared after an arousal/awakening (a type 3 event). The remaining 7 events were cleared without an arousal from sleep. This latter event does not fall into the 3-type classification of Dent et al. and indicates the presence of a fourth type of event, one in which reflux occurs and is cleared during sleep, possibly through the effects of secondary peristalsis because the swallowing reflex and primary peristalsis are suppressed (39,40).

A secondary finding of this study was that there was no difference in subjective (ESS) sleep quality between those who experienced nGER episodes and those who did not. These findings are in contrast with previous studies that generally report a detrimental effect of nGER on subjective sleep quality (1,2,4,41–44). It is not known why our data regarding subjective sleep quality differ from that in other studies; however, data from the present study suggest that nGER does not necessarily underlie fragmentation of sleep, as has been suggested previously (16,43,45). In addition, we showed no difference in objective measures of sleep quality (sleep efficiency, wake time after sleep onset, ArI, and AwI) between those who experienced nGER episodes and those who did not. Published data regarding the association between nGER and objective measures of sleep quality (PSG or actigraphy) are less consistent than that for subjective sleep quality with some studies reporting improvements in objective sleep quality, with nGER therapy (14,36,46), but others reporting no effect (16,43,45). It has been reported previously that there is a poor correlation between objective measures of GER and subjective GER symptoms (47–51), something which we also note here, with only 50% of individuals with objectively assessed nGER episodes reporting nGER symptoms and 56% of those without objectively assessed nGER reporting nGER symptoms.

Individuals with OSA had significantly more nGER that those without OSA, during the daytime and nocturnal periods. The tendency for individuals with OSA to have more severe reflux has been reported previously (45,52–55). It is possible that arousals and awakenings that occur within normal sleep are permissive factors for TLESRs, which are known to underlie most of the GER events and have also been shown to be more frequent overnight in individuals with OSA (38). If this is the case, the increase in arousals and awakenings characteristic of OSA may underlie the increased number of nGER events in these individuals. The reason for the increased GER events during the daytime period is uncertain; however, this may be due to the higher BMI in the OSA group than the non-OSA group because a higher BMI is related to both more severe GER and an increase in TLESR frequency (56).

Limitations

This study has several limitations. First, a large proportion of our subjects had OSA, despite the fact that they were not recruited on such a basis. At least in part, this reflects the high proportion of OSA in the general population with a recent study suggesting that 23% of women and 50% of men have the disorder (57). The group with OSA were also older and more obese and therefore may have influenced the findings. However, the presence of such subjects assured a substantial number of overnight arousal/awakenings (albeit often upper airway obstruction related) with which to related to the occurrence of nGER events. Future studies in this field could consider screening for OSA before the study enrollment to apportion OSA and non-OSA subjects differently. Second, a “relatively” lean population was studied, with mean BMI of 28 kg/m2. Because obesity is known to be a major risk factor for GER, it is possible that the results of this study may not be generalizable to obese/morbidly obese populations. Third, BMI was different between the OSA and non-OSA groups. Although such a difference may influence comparison of these 2 groups, BMI was not different between those with and without nGER; as such, the BMI difference between the OSA groups was unlikely to influence the major study conclusions. Fourth, the data were collected in the sleep laboratory of a tertiary hospital and therefore may not be reflective of “natural” conditions. In addition, PSG and pH-impedance monitoring are limited in their ability to assess day-to-day variability in sleep quality and nGER occurrence because they involve short-term monitoring. However, the primary purpose of this study was to assess the temporal relationship between arousal and nGER events, rather than examine patterns of symptom associations over longer time periods. The controlled conditions of a sleep laboratory provide an optimal environment in which to make such an assessment. Finally, it is possible that sleep quality is adversely affected in individuals with more severe nGER and our cutoff of any nGER episodes was not sensitive enough to capture this. A larger sample size would be required to examine the relationship between severity of nGER and sleep quality.

CONCLUSIONS

This study used gold-standard in-laboratory PSG to assess the temporal relationships between nGER events and arousal from sleep. It demonstrated that most of the nGER events not only occur and are cleared during periods of wakefulness after sleep onset but also are generally preceded by arousal or awakening from sleep, suggesting that arousal may be a precipitator of nGER. This study also suggests that OSA is associated with an increase in nGER events, possibly because of an increase in periods of arousal or wakefulness from sleep which are characteristic of OSA and which seem to underlie most of the nGER events.

CONFLICTS OF INTEREST

Guarantor of the article: Peter Eastwood, BSc, PhD.

Specific author contributions: K.S.: study design and oversight, data collection, data analysis, and manuscript preparation. J.O.: subject recruitment, data collection, and editing of the final manuscript. V.G.: subject recruitment, data collection, and editing of the final manuscript. R.H.: study design, data interpretation, and editing of the final manuscript. D.H.: study design, data interpretation, and editing of the final manuscript. P.E.: study design and oversight data interpretation and manuscript preparation. All authors have approved the final draft of the manuscript for submission.

Financial support: This study was funded by a National Health and Medical Research Council Project Grant (No. 10316178). P.E. is supported by a NHMRC Senior Research Fellowship (No. 1136548).

Potential competing interests: None to report.

Trial registration: This trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12612000458831).

Study Highlights

WHAT IS KNOWN

  • ✓ nGER generally occurs in association with arousal or awakening from sleep.

WHAT IS NEW HERE

  • ✓ Arousal and awakening from sleep were more likely to precede than follow nGER events, suggesting that reflux events are precipitated by arousal from sleep rather than the converse.
  • ✓ nGER does not affect sleep quality.

ACKNOWLEDGEMENTS

The authors would like to thank the staff of the West Australian Sleep Disorders Research Institute at Sir Charles Gairdner Hospital for their assistance with this study.

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