SEARCH

SEARCH BY CITATION

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion – part I: overall patterning of sleep period reflux and oesophageal acid clearance
  6. Results and discussion – part II: sleep state and antireflux function at the time of reflux
  7. Conclusions
  8. Authorship
  9. Acknowledgements
  10. References

Background

Gastro-oesophageal reflux disease (GERD) adversely impacts on sleep, but the mechanism remains unclear.

Aim

To review the literature concerning gastro-oesophageal reflux during the sleep period, with particular reference to the sleep/awake state at reflux onset.

Methods

Studies identified by systematic literature searches were assessed.

Results

Overall patterns of reflux during the sleep period show consistently that oesophageal acid clearance is slower, and reflux frequency and oesophageal acid exposure are higher in patients with GERD than in healthy individuals. Of the 17 mechanistic studies identified by the searches, 15 reported that a minority of reflux episodes occurred during stable sleep, but the prevailing sleep state at the onset of reflux in these studies remains unclear owing to insufficient temporal resolution of recording or analysis methods. Two studies, in healthy individuals and patients with GERD, analysed sleep and pH with adequate resolution for temporal alignment of sleep state and the onset of reflux: all 232 sleep period reflux episodes evaluated occurred during arousals from sleep lasting less than 15 s or during longer duration awakenings. Six mechanistic studies found that transient lower oesophageal sphincter relaxations were the most common mechanism of sleep period reflux.

Conclusions

Contrary to the prevailing view, subjective impairment of sleep in GERD is unlikely to be due to the occurrence of reflux during stable sleep, but could result from slow clearance of acid reflux that occurs during arousals or awakenings from sleep. Definitive studies are needed on the sleep/awake state at reflux onset across the full GERD spectrum.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion – part I: overall patterning of sleep period reflux and oesophageal acid clearance
  6. Results and discussion – part II: sleep state and antireflux function at the time of reflux
  7. Conclusions
  8. Authorship
  9. Acknowledgements
  10. References

Impairment of sleep quality by night-time reflux symptoms

Impairment of sleep quality by night-time reflux symptoms is well documented by studies that have found that gastro-oesophageal reflux disease (GERD) is associated with perceived interruptions of sleep, fatigue and consequent impaired work productivity.[1-3] Results from a placebo-controlled trial of patients troubled by nocturnal heartburn and regurgitation have shown that there are significant improvements in patient-assessed sleep quality in participants treated with proton pump inhibitors, suggesting that reflux, in particular acid exposure, contributes directly to impairment of sleep.[4] These findings provide strong logic for conducting mechanistic studies to evaluate the detailed patterning or ‘architecture’ of distinct sleep stages, arousals and awake periods in patients with GERD, and to relate these sleep monitoring data to the onset of reflux, to symptoms and to the subsequent clearance of the refluxed acid. More accurate insights provided by such mechanistic studies could provide the basis for development of better targeted interventions on the events that lead to reflux-induced sleep fragmentation.

Evaluations of the relationship between sleep state and occurrence of reflux

Evaluations of the relationship of sleep state to occurrence of reflux agree that arousals and awakenings from sleep are closely associated with reflux episodes. However, it is important to recognise that any such association could be a reflection of the large number of arousals that normally occur during sleep. For example, the frequency of arousals varies from 4 to 26 per hour, depending on the scoring criteria used,[5] and increases with age, from 11 per hour in individuals aged 18–20 years to 22 per hour in those aged 61–70 years.[6] Therefore, there exists a high probability, by chance, of a reflux event occurring in proximity to any given arousal or awakening.

Precise timings and occurrences of arousals and awakenings can only be obtained by polysomnography, which requires concurrent recording of the electroencephalogram (EEG), the submental electromyogram (EMG) and the electro-oculogram (EOG). The EOG captures the speed and pattern of eye movements, allowing recognition of rapid eye movements (REMs), which, in combination with silence on the EMG tracing and low-amplitude, high-frequency EEG readings, indicates REM sleep. Nonrapid eye movement (NREM) sleep, the second major category of sleep, is subdivided into three or four depth stages mainly on the basis of the EEG pattern.

Evaluation of sleep/awake patterns can also be obtained using actigraphy. An actigraph is a wrist-watch-like data logger device attached to the wrist of the nondominant arm that detects movements with accelerometers and records the timings.[7] No other variables, such as EEG or EMG, are recorded. Documented periods of stillness during the sleep period are taken to indicate sleep and the occurrence of body movements is taken to indicate interruptions of stable sleep. Actigraphy is a useful method for investigating group differences, gross sleep-pattern variations over time and the effects of behavioural or treatment interventions,[8, 9] as long as the recording period is long enough to provide reliable measures.[10, 11] However, it has significant limitations for the detailed assessment of the mechanistic relationship between sleep and reflux: wakefulness during the sleep period has been detected by actigraphy for only about 35–50% of polysomnographically detected awake time.[12-17]

Arousals and awakenings are variably defined

Arousals and awakenings have been variably defined. This presents a significant practical issue for review of their relationship with reflux events. Some reports use these terms interchangeably (i.e. an awakening having the same criteria as an arousal), whereas others define an awakening as a period of wakefulness that occupies at least half of the time of the epoch(s) in which it occurred (i.e. at least 15 or 30 s of the most commonly used 30- or 60-s epochs), an approach that will recognise only some awakenings and no arousals. The most accurate approach to the recognition and scoring of arousals and awakenings is to use a second-by-second analysis of the polysomnography recording. Using this method, an arousal is widely defined as a disturbance of stable sleep lasting between 3 and 15 s that has an alpha EEG rhythm. A 3-s minimum duration is a pragmatic cut-off,[18] but Younes and coworkers[19, 20] defined even brief (>1.5 s) high-frequency EEG shifts as arousals because these appear to be relevant to the abrupt resolution of obstructive respiratory events and so may also be relevant to the onset of some reflux episodes. An awakening is taken as a disturbance of stable sleep that lasts for more than 15 s. Hence, an awakening will always start as an arousal.

Three major possible mechanistic scenarios

Three major possible mechanistic scenarios could underlie fragmented sleep in GERD and the universally observed close temporal relationship between arousals/awakenings and reflux onset. These are illustrated schematically in Figure 1 and are not necessarily mutually exclusive. The first and most widely accepted mechanistic possibility is that reflux occurs during sleep, causing oesophageal sensations that provoke arousals/awakenings, as illustrated in Figure 1a. It is possible, however, that some, maybe many, arousals/awakenings thought to be triggered by reflux could be unrelated to it and may occur by chance as part of the normal architecture of sleep.

image

Figure 1. Schematic illustration of three possible scenarios for the timing of reflux onset in relation to arousals or awakenings. Swallows are shown, but for simplicity, oesophageal body pressures are not included. The sleep analysis summarised in the top row of each scenario represents a second-by-second scoring of sleep or arousals/awakenings. (a) Reflux during stable sleep. Reflux occurs shortly before sleep and is then interrupted by an awakening. In this scenario, it has been assumed that the awakening has been provoked by reflux-induced sensations. (b) Reflux during arousals/awakenings. In this scenario, it is proposed that arousal or awakening is the permissive event that allows occurrence of motor events that trigger reflux. In this case, the arousal/awakening preceded the occurrence of reflux onset, so it cannot be considered to have been triggered by reflux. Rather, the arousal is most likely to be consistent with the normal architecture of sleep. Some reflux episodes are associated with arousals that last only a few seconds (see Figure 1c and Figure 2): in such cases, the motor events that lead to reflux may still be evolving when sleep is resumed, so that reflux onset may occur after return to sleep. (c) Prolonged oesophageal acidification leading to arousals/awakenings. This schematic encompasses a 20-min period, but only illustrates 10 min of recording, with the time between 5 and 15 min excised. During this excised period, there was no reflux or swallowing and stable sleep persisted throughout. Reflux occurs according to the scenario shown in Figure 1b, except that it happens during an arousal that lasts for just under 15 s. There is only one swallow following reflux before sleep resumes and, as a result, acid clearance fails because swallowing does not occur during the subsequent 16.5-min period of stable sleep. Oesophageal pH remains below 4 until it is cleared by swallowing during the next awakening. It is possible that this prolonged period of oesophageal acidification leads to heartburn or chest pain, which then triggers the awakening.

Download figure to PowerPoint

The second possible scenario is that reflux occurs during arousals/awakenings (Figure 1b). In this circumstance, the change in sleep state cannot be a consequence of the reflux that follows: rather, it is possible that arousals/awakenings are permissive factors for the motor changes that lead to reflux.

The third possible scenario (Figure 1c) is that sleep is disrupted by the development of heartburn minutes after the onset of reflux when there has been a failure of oesophageal acid clearance. In this situation, prolonged periods of oesophageal acidification occur when there is an early resumption of stable sleep when oesophageal pH is still low after a reflux episode: acid clearance does not occur with resumption of sleep because of sleep-related suppression of swallowing and salivation, the normal acid clearance mechanism.[21-25] Even in healthy individuals, this scenario can lead to very prolonged exposure of the oesophageal mucosa to noxious gastric content (Figure 2). Experimental infusions into the oesophagus during stable sleep support this third scenario of sleep-induced prolonged failure of oesophageal acid clearance as a plausible cause of fragmentation of sleep, especially in patients with reflux disease.[22, 23] Arousals occurred significantly more frequently and earlier with intra-oesophageal infusions of acid during stable sleep than with infusions of water. Patients with reflux disease also had a significantly shorter latency to acid-infusion-associated arousal than healthy volunteers, probably because of acid sensitivity of the oesophageal mucosa caused by high levels of daytime reflux.[23] A study by Orr and Johnson in healthy individuals showed that the lower the pH of the infusate used, the shorter the latency to arousal.[26]

image

Figure 2. Manometric and pH recording in a healthy individual made during polysomnography, which was scored on a second-by-second basis for sleep and arousals/awakenings, as shown in the top panel. The spikes in the pharyngeal pressure trace are generated by swallowing. LOS pressure was monitored with a sleeve sensor. The first recorded swallow occurred at the start of an awakening from sleep. During this awakening, there was abrupt acidification (dashed line) of the distal oesophagus during a typical transient LOS relaxation that started about 15 s after the second swallow and was not causally related to it. Offset of the transient relaxation is associated with a feeble synchronous oesophageal body contraction that has no discernible effect on oesophageal pH. Even though the recovery of LOS pressure makes it impossible for further reflux to occur, oesophageal pH remained well below 4. Subsequent swallow-induced peristalsis, still during the awakening, caused a minor degree of acid clearance, after which the subject returned to sleep; during this sleep interval (about 5 min of which is shown in the figure), there was a slow upward drift of pH. Beyond the time shown in the figure, the sleep interval lasted for just over 20 min, without any swallowing and with maintenance of the LOS pressure barrier: during this time, oesophageal pH remained below 4. The next arousal resulted in effective acid clearance because it was associated with several swallows and peristalsis. Note that small, irregular pressure waves not related to respiration were recorded in the stomach pressure tracing during the awakening before and just after reflux onset. These were caused by nonrespiratory body movements and indicate that this particular awakening would have been recognised by actigraphy. Probably, actigraphy would have scored the last swallow of the awakening as having occurred during sleep, because awake stillness dominated this time period. Adapted from Dent et al.[21] with permission. LOS, lower oesophageal sphincter.

Download figure to PowerPoint

Currently, there is disagreement in the literature on whether arousals/awakenings are triggered by reflux or vice versa. This article reviews the literature that provides data on the overall patterning of sleep period reflux, the possible relationships between sleep state and the occurrence of reflux during the sleep period, and how reflux disease could cause fragmentation of sleep.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion – part I: overall patterning of sleep period reflux and oesophageal acid clearance
  6. Results and discussion – part II: sleep state and antireflux function at the time of reflux
  7. Conclusions
  8. Authorship
  9. Acknowledgements
  10. References

Systematic literature searches were conducted in PubMed and Embase on 25 May 2010 and were updated on 4 January 2012 to identify studies on the relationship between sleep and measures of gastro-oesophageal reflux. The following search string was used: (‘Sleep’ OR ‘nocturnal’ OR ‘nighttime’ OR ‘night’ OR ‘supine’ OR ‘recumbent’ OR ‘arousal’) AND (‘gastroesophageal reflux’ OR ‘gastro-oesophageal reflux’). The search update also included the terms ‘acid clearance’ OR ‘esophageal acidification’ OR ‘oesophageal acidification’. Search filters were applied to exclude reviews and studies conducted in children. The remaining studies were screened manually based on titles and abstracts, and the full article was examined when the relevance of the study was not clear from the abstract. Commentaries and editorials were excluded, as were studies in children and reviews that had not been eliminated by the search filters.

Studies were included if they evaluated the temporal relationship between sleep state and reflux episodes. Supporting studies reporting on the overall patterns of oesophageal acid exposure during awake and sleep periods were also included where relevant. A flow chart of the systematic searches is shown in Figure 3.

image

Figure 3. Flow chart of literature searches. The systematic searches identified 17 studies about the relationship between reflux episodes and sleep/awake state.

Download figure to PowerPoint

Results and discussion – part I: overall patterning of sleep period reflux and oesophageal acid clearance

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion – part I: overall patterning of sleep period reflux and oesophageal acid clearance
  6. Results and discussion – part II: sleep state and antireflux function at the time of reflux
  7. Conclusions
  8. Authorship
  9. Acknowledgements
  10. References

The systematic literature searches identified 17 publications that evaluated the temporal relationship between sleep state and individual reflux episodes (Table 1).[2, 21, 24, 27-40] These are presented and discussed in Part II of the Results and Discussion. For studies identified as addressing other aspects of the relationship between reflux and sleep, only those judged to provide key information relevant to understanding of the mechanistic studies are cited and discussed below.

Table 1. Mechanistic sleep/reflux studies identified by the literature review
ReferenceOesophageal reflux detection methodReflux onset related to sleep state?Temporal resolution of reflux recordingParticipantsProportion of reflux episodes during sleepLOS functionSleep recording/analysis methodsComments
  1. GER, gastro-oesophageal reflux; GERD, gastro-oesophageal reflux disease; LOS, lower oesophageal sphincter; NR, not reported; OSA, obstructive sleep apnoea; RO, reflux oesophagitis; TLOSR, transient lower oesophageal sphincter relaxation.

  2. Actigraphy was used in references [38] and [39]; polysomnographic epoch-based analyses were used in references [2], [27-37] and [40]; at least predominantly second-by-second analyses of sleep and reflux were employed in references [21] and [24].

  3. a

    Impedance-detected reflux.

Poh et al., 2010[38]pHNoDigitisation every 5 s

Healthy: n = 9;

GERD: n = 39

No data

14.4% (see Comments)

Not assessedActigraphy, epochs (?) (see Comments)Only ‘conscious’ awakenings (>2 min) evaluated. Actigraphic analysis criteria not stated
Poh et al., 2010[39]pHNoProbably digitisation every 5 sGERD: n = 39‘Some’Not assessedActigraphy, epochs (?) (see Comments)No systematic analysis of sleep state and sleep period reflux. Actigraphic analysis criteria not clear
Di Marino et al., 2005[27]pHNot statedInadequate informationGERD: = 8; disturbed sleep, no GERD: = 8NR/53Not assessedPolysomnography, epochsAll sleep period reflux episodes associated with (‘occurring 5 min before sleep event’) arousal/awakening
Dickman et al., 2007[2]pHNot statedNot stated

GERD: = 15

(11 RO)

13/39 (33%)Not assessedPolysomnography, epochs19/21 ‘asleep’ reflux episodes followed by arousals or awakenings in next epoch
Orr et al., 2008[33]pHYesNot statedPoor sleep, no heartburn: = 81; normal sleep, no heartburn: = 3943/80 (54%)Not assessedPolysomnography, epochsNo data on relationships between arousals/awakenings and reflux episodes
Kuribayashi et al., 2010[34]pH manometryYes<1 sOSA and RO: = 837/82 (45%)41% during TLOSRsPolysomnography, epochs, and arousals and awakeningsArousals/awakenings <1 min before or after reflux in 46/67 ‘asleep’ reflux episodes. Arousals scored, but no systematic analysis given on their relationship to onset of all reflux episodes
    OSA without RO: = 99/30 (30%)78% during TLOSRs
  Healthy: = 810/45 (22%)50% during TLOSRs
Kuribayashi et al. 2009[28]pH impedance manometryNot statedRapid digitisation, rate not reportedHealthy: = 1522/76 (29%)a‘Asleep’ reflux episodes all during TLOSRs (see Comments)Polysomnography, epochs, and arousals and awakeningsAnalysis concentrated on TLOSRs. All of the 76 impedance-detected reflux episodes appear to have been during TLOSRs. Not explicitly stated that this was the only mechanism of reflux
Kuribayashi et al., 2010[35]pH impedance manometryYesRapid digitisation, rate not reportedGERD: = 925%a (estimate)‘Asleep’ reflux episodes all during TLOSRs (see Comments)Polysomnography, epochs. No data on arousals or awakenings relative to refluxAnalysis concentrated on TLOSRs and sleep apnoea episodes. Not explicitly stated whether TLOSR was the only mechanism of reflux
  OSA without GERD: = 6;13%a (estimate)
OSA and GERD: = 11;14%a (estimate)
healthy: = 1533%a (estimate)
Penzel et al., 1999[29]pHNot stated2 s

Suspected OSA: n = 15

(of whom n = 5 with reflux symptoms)

52/69 (75%), but 68/69 (99%) associated with arousalNot assessedPolysomnography, epochs, but also detailed assessment for arousals/awakeningsOne reflux episode definitely occurred during stable sleep
Ing et al., 2000[30]pHNot statedNot stated

Suspected OSA: n = 63;

controls: n = 41

Unclear from reported dataNot assessedPolysomnography, analysis not describedData for temporal relationship between sleep state and reflux is unclear
Cohen et al., 2003[31]pHNot statedDigitisation 12 × per second

GERD: n = 11;

controls: n = 7

54%Not assessedPolysomnography, epochsLimited details on analysis methods. Found no association of reflux with arousals.
Mello-Fujita et al. 2008[37]pHYesNot stated

Asthma: n = 31;

controls with sleep disturbance: n = 31

Up to 43%Not assessedPolysomnography, epochsData tabulation unclear
Gagliardi et al., 2009[40]pHNoNot stated

Controls: n = 8;

GERD: n = 15

Unclear from reported dataNot assessedPolysomnography, epochsOccurrence of reflux during sleep implied but detailed mechanistic data not provided
Shepherd et al. 2011[36]pH manometryYes1 sPatients with OSA and nocturnal GER22%40% of nocturnal GER due to TLOSRsPolysomnography, epochsLimited evaluation of temporal relationship between nocturnal GER events and arousals from sleep
Suzuki et al., 2010[32]pHNot stated1 sSuspected OSAs: n = 61 (of whom n = 37 with GERD)>90% associated with arousalsNot assessedPolysomnography, epochsAnalysis did not determine whether arousals preceded or followed onset of reflux episodes
Freidin et al., 1991[24]pH manometryYes<1 sHealthy: = 11;2/6 (33%)No dataPolysomnography, epochs‘Asleep’ reflux episodes not re-evaluated by second-by-second sleep analysis
GERD (RO): = 110/105 (0%)42/105 (40%) episodes scored as occurring during TLOSRsPolysomnography, initially epochs, then second-by-second in GERD3/10 episodes scored by the epochal analysis were not re-evaluated with second-by-second analysis, so have been subtracted from the total 105 acid reflux episodes
Dent et al., 1980[21]pH manometryYes<1 sHealthy: = 10 (two consecutive days)0/130 (0%)266/272 (98%) during TLOSRsPolysomnography, second-by-secondNo numerical tabulation of sleep/awake state data in relation to onset of reflux. Data refer to an awake period of about 3 h, as well as the 8-h sleep period. Sleep was monitored only during the second night

Patterns of oesophageal acid exposure and numbers of reflux episodes during awake and sleep periods

Interpretation of the literature on overall patterns of day/night reflux should take into account two major factors that are likely to influence them during the sleep period independently of physiological changes directly attributable to sleep. First, the sleep period is usually a prolonged time of fasting. Food intake, especially a large meal, is a potent stimulus for reflux. Secondly, it is possible that different recumbent body positions (i.e. supine, left lateral, right lateral or prone) could affect the risk of occurrence of reflux, but we are not aware of any data that investigate this possibility in adults during sleep. Furthermore, relative to upright, the recumbent body position has been shown to inhibit the occurrence of transient lower oesophageal sphincter (LOS) relaxations and to reduce numbers of reflux episodes and consequent oesophageal acid exposure when food intake is taken into account.[41] These nonsleep influences complicate evaluations of the effects of sleep alone on reflux.[42]

Data on oesophageal acid exposure for the sleep period vs. daytime can be safely compared among studies, as this measure is derived with a standard approach. This is not the case for the frequently reported data on reflux episode numbers or frequency. There are major differences in the pH and duration criteria used to score occurrence of a reflux episode among all pH monitoring studies and, in particular, those that deal with the sleep period. Consequently, valid comparisons of data on reflux frequency can only be made within a single study or across studies that use the same pH/duration criteria. The advent of impedance monitoring, which detects all reflux episodes regardless of pH, has established that many reflux episodes do not result in a recognisable pH change.[43]

Healthy individuals

Under normal conditions of food intake and daytime physical activity, the literature is consistent in showing that acid exposure is substantially lower during the sleep period than in the awake period.[7, 25, 44] This effect is primarily due to a much lower frequency of reflux episodes during the sleep period than prior to the first onset of sleep.[7, 25, 44, 45] Impedance monitoring has revealed that traditional acid reflux episodes (pH <4) account for a minority of all sleep period reflux episodes and a median of 80% of these episodes are weakly acidic (drops of pH that do not go below 4[43]).[44]

Patients with reflux disease

At night, most reflux in patients with GERD occurs during the first half of the sleep period.[24, 25, 46, 47] A within-study comparison found that, during the sleep period, patients with reflux oesophagitis had both an increased frequency of reflux episodes overall and longer acid clearance times than healthy volunteers.[25] The single measure of sleep period reflux that best distinguishes reflux oesophagitis from non-erosive reflux disease appears to be the number of reflux episodes with prolonged clearance (>5 min).[48]

In their recent pH/impedance study, Fornari et al.[44] found that patients with GERD have three times more sleep period reflux episodes of all types (i.e. regardless of pH) than healthy individuals. Also, a larger proportion of reflux episodes was acidic in patients with GERD compared with healthy individuals (median proportion with pH <4: 43% vs. 20% respectively). In patients with reflux disease, the proportion of weakly acidic reflux episodes rose steadily from about 33% in the first recumbent hour to approximately 70% in the last recumbent hour.

For individuals with non-erosive reflux disease and mild [Los Angeles (LA) grade A or B] reflux oesophagitis, acid exposure levels during sleep are relatively low compared with those occurring during the awake period, so that the 24-h pattern of acid exposure resembles that of healthy individuals, albeit at a higher level.[49] In contrast, in the small minority of patients with severe reflux oesophagitis (LA grade C or D), the day/night pattern of reflux differs substantially from that found in patients with less severe reflux disease and in healthy subjects. Patients with severe oesophagitis have very high levels of night-time acid exposure that may, in some cases, be similar to the very high daytime levels seen in this GERD subgroup.[49-51]

Oesophageal acid clearance during the sleep period

The combined suppression of salivation and swallowing during the sleep period can greatly reduce the rate at which the oesophageal luminal pH recovers to a non-injurious level above 4 following acid reflux (Figure 2). During arousals and awakenings, there is frequently a cluster of swallowing and oesophageal body peristalsis, so that provided the arousal/awakening is of sufficient duration, clearance of any oesophageal acidification is usually rapid (Figures 1a,b and 4).[34]

image

Figure 4. Tracing of oesophageal motility (LOS pressure monitored with a sleeve sensor) and pH with superimposed sleep and apnoea analyses (polysomnographic raw tracing not shown) in a patient with obstructive sleep apnoea. This illustrates the potential for physiological and temporal complexity of sleep, arousals, oesophageal motility, apnoea and body movements around the time of a sleep period reflux episode. The sleep analysis at the bottom of the figure used the epochal approach. Three arousals occurred, as shown at the top of the figure, but they were too short to be reflected in the epochal sleep analysis. The transient LOS relaxation that leads to GER, although associated with a brief arousal, would have been scored by the epochal method as starting during stable REM sleep. Adapted from Kuribayashi et al.[34] with permission. GOJ, gastro-oesophageal junction pressure; GER, gastro-oesophageal reflux; LOS, lower oesophageal sphincter; MVT, movement; REM, rapid eye movement; S1, sleep stage 1; TLOSR, transient lower oesophageal relaxation.

Download figure to PowerPoint

Healthy individuals

Oesophageal acid clearance times in healthy subjects indicate that individual reflux episodes during the sleep period result in a very wide range of acid exposure times and a longer average time for recovery of oesophageal pH to 4 compared with during the daytime.[21, 25] Monitoring of swallowing, oesophageal body motility, sleep and oesophageal pH in healthy individuals has shown how the sleep-related absence of swallowing can lead to long oesophageal acidification times following reflux during the sleep period (Figure 2).[21]

Patients with reflux disease

The study by Dodds et al.,[25] in 20 patients with reflux oesophagitis, and 15 healthy control subjects, provides detailed comparative data on patterns and mechanics of oesophageal acid clearance. Consistent with other studies of clearance during wakefulness, acid clearance time is, on average, substantially longer in patients with GERD than in controls. Dodds et al. found that clearance of reflux episodes during wakefulness was more than three times longer in patients with reflux oesophagitis than in healthy controls.[25] Unfortunately, because sleep was not monitored formally in this study, detailed data are not available on the interaction of resumed sleep after a reflux episode during the sleep period. However, for the night-time recording period, very prolonged periods of acidification were seen, so that oesophageal acid clearance to pH 4 took longer than 5 min in 15% of reflux episodes in the patients with oesophagitis and in 9% of reflux episodes in the control subjects. Even longer periods of acidification of at least 10 min accounted for 6% and 3% of the episodes in the patients with oesophagitis and the controls respectively. The rate of swallowing during individual periods of acidification varied widely, but differed little overall between the two groups. For individual episodes, swallow frequency correlated with acid clearance time, but the much higher rate of failure of swallow-induced peristalsis in patients with oesophagitis (27% vs. 7% in controls) is a plausible major contributor to the slow acid clearance in the patients with oesophagitis. Suppression of primary peristalsis because of resumption of sleep before acid clearance was completed is likely to have augmented the effect of failed primary peristalsis on acid clearance. A ‘pronounced’ failure of triggering of secondary peristalsis in response to oesophageal distension has been documented in daytime studies in patients with GERD.[52] The finding of Dodds et al.[25] that, in patients with oesophagitis, secondary peristalsis was the first oesophageal body motor event following reflux in only 17% of episodes, compared with 57% in the controls, suggests that failed triggering of secondary peristalsis also contributes to the slow acid clearance seen in GERD.

Given the evidence that slow acid clearance is likely to play a significant role in provocation of sleep period reflux symptoms, it is of interest to note that bed head elevation or sleeping on a wedge has been shown consistently to be associated with a modest reduction in sleep period oesophageal acid exposure when compared with sleeping recumbent. This occurs because of reduction in the time taken for oesophageal acid clearance, presumably because of the effects of gravity.[53, 54] Unfortunately, this effect appears too small to result in a major reduction in sleep period symptoms when used on its own. None of the studies sought to determine whether sleep quality was improved by postural therapy.

Polysomnography was used by Freidin et al.,[24] in their study of patients with GERD, but minimal data are presented on events relevant to clearance. Studies that monitor and correlate sleep, oesophageal pH, occurrence of symptoms and oesophageal motor events in well-characterised patients with GERD and healthy controls are needed. These would be likely to advance substantially the mechanistic understanding of factors that contribute to the development of reflux-induced symptoms during the sleep period.

Factors determining the development of reflux-induced symptoms during the sleep period in reflux disease

Apart from the sleep period oesophageal acid infusion studies of Orr and colleagues (see 'Introduction'),[22, 23, 25] our searches did not reveal any detailed analyses of the characteristics of sleep period reflux episodes that are associated with reflux-induced symptoms, by comparison with the great majority of episodes that are asymptomatic. The acid infusion studies indicate that both the duration of oesophageal acid exposure arising from a single acidification episode[22, 23] and the pH of the refluxate[26] are relevant. Studies of the association of symptoms with individual reflux episodes in the awake state by Bredenoord et al.[55] are consistent with the findings of Orr et al.,[22, 23, 26] in that a high cumulative level of prior acid exposure, larger drops of pH to lower nadirs, higher extent of flow of refluxate up the oesophagus and prolonged clearance times were associated with symptomatic reflux episodes, compared with asymptomatic episodes. We have found no such data in relation to the sleep period. This is an area of research that merits attention.

Results and discussion – part II: sleep state and antireflux function at the time of reflux

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion – part I: overall patterning of sleep period reflux and oesophageal acid clearance
  6. Results and discussion – part II: sleep state and antireflux function at the time of reflux
  7. Conclusions
  8. Authorship
  9. Acknowledgements
  10. References

Important methodological considerations

Transitions from sleep to arousals and awakenings occur within 1 s (Figure 2), sometimes with considerable temporal complexity (Figure 4).[21, 34] It is important to document these events from second to second around the time of reflux onset because of the general agreement that arousals/awakenings are closely associated with the timing of reflux. Accurate resolution of the timings of both sleep state and reflux onset is required to determine whether arousals/awakenings could be triggered by reflux or vice versa.

Factors influencing the accuracy of reflux episode timing measurements

The time of onset of reflux is the pivot point for determining the relationship between sleep state and the occurrence of reflux. In seven of the 17 studies investigating this relationship (Table 1), the onset of reflux was used as the reference time for correlations with sleep.[21, 24, 33-37] Three other studies appear to have taken the entire time that oesophageal pH was below 4 as the reference period.[38-40] In the remaining seven studies, the criteria used to judge the timing of reflux from the pH tracing were not stated,[2, 27-32] thus data on the relationship between the reflux events and sleep cannot be adequately evaluated in these studies.

The three mechanistic studies that used the total time the pH was below 4 to define reflux referred to this as the ‘duration’ of reflux,[38, 39] or as a ‘reflux event’.[40] These terminologies fail to distinguish between the event of reflux and the impacts on oesophageal pH that persist after cessation of flow across the gastro-oesophageal junction. The true period of reverse flow of gastric contents into the oesophagus usually occurs over only a few seconds, being cut off by the prompt re-establishment of the gastro-oesophageal junction pressure barrier, which is normally contributed to by the LOS and diaphragmatic crura (Figure 2). Importantly, this cessation of flow usually occurs considerably earlier than the return of the pH to 4, meaning that the true onset of reflux cannot be accurately defined with such an approach. A more correct description of the time taken for the pH to return to 4 is ‘oesophageal clearance time’ or ‘duration of oesophageal acidification’.

Another potential source of temporal inaccuracy when defining reflux onset arises from the use of early digital pH recording systems with slow sampling rates, often as low as one pH value every 5 s (Table 1). Such a sampling rate could delay recognition of the onset of a reflux episode by up to 5 s: this is a significant limitation when attempts are made to align reflux events temporally with other, frequently rapidly evolving, physiological events such as an arousal from sleep. Of the 14 studies in which the pH trace was digitised,[2, 27-33, 35-40] a 5-s digitisation interval was explicitly stated as being used in one publication,[38] and was probably also used in another report by the same group.[39] In another six studies, the stated digitisation rate was suited to mechanistic sleep studies as pH was sampled at least every 2 s (Table 1).[28, 29, 31, 32, 35, 36] In three studies, the analogue signal was recorded from the pH monitoring equipment, capturing a true second-to-second pH record.[21, 24, 34]

Methods used for analysis of sleep state around the time of reflux onset in sleep and reflux studies

The standard, pragmatic method used to gain an overview of sleep architecture over the entire sleep period for actigraphic and polysomnography recordings is a time block or epochal analysis. In the case of actigraphy, the only possible judgement to make is whether body movement (the proxy for awake) or stillness (the proxy for sleep) predominates within each epoch. In the case of polysomnography, a single stage of sleep or wakefulness is assigned to each epoch by identifying the sleep state that occupies the most time within each epoch. Polysomnographic analyses have used a range of epoch lengths, mainly from 20 to 60 s. Importantly, arousals and shorter periods of awakening are not recognised by this routine epoch-based reporting method (Figure 4). Thus, an epoch classified as sleep could contain significant unscored intervals of wakefulness or arousals. A reflux episode that occurs during such an epoch would, however, be scored as taking place during sleep even if its onset was during an arousal, or towards the end of an awakening. It follows that mechanistic studies of sleep and reflux using polysomnography require a special approach to sleep analysis that evaluates the sleep state on a second-by-second basis around the time of onset of each reflux episode. Only two of the 17 studies examining the relationship between reflux episode and sleep state used this approach to derive their main reported data.[21, 24] Five other studies, however, supplemented an epochal sleep analysis with a second-by-second approach (as shown in Figure 4) to define the timings of arousals/awakenings, but did not report data derived with this alternative approach in adequate detail to determine sleep state reliably at the time of reflux onset.[28, 29, 34-36]

Mechanistic studies of sleep and reflux using actigraphy

The two actigraphic studies discussed below evaluated patterns of reflux only around periods of awakening >2 min, which were called ‘conscious’ awakenings.[38, 39] The rationale for such a classification was that these awakenings are able to be recalled at the end of the sleep period, while awakenings shorter than 2 min are not.[38, 39] This approach is unfortunately not supported by the publications cited to justify this subdivision of awakenings.[56, 57] Quite apart from the validity of the concept of ‘conscious’ awakenings, it is illogical for this subdivision to determine which periods of a recording should be analysed for the relationships between sleep and reflux.

Healthy individuals

We identified one pH/actigraphic study, by Poh et al., from which data were published on the relationship between sleep state and reflux in healthy volunteers.[38] Nine individuals were studied and the analysis was limited to ‘conscious’ awakenings (see above). While such awakenings were detected in seven of the nine participants, no acid reflux episodes were recorded during these times.

Patients with reflux disease

A total of 39 patients with GERD were evaluated in two actigraphic studies.[38, 39] These papers, from the same research group, probably refer to the same patient population, although this is not explicitly stated. In one study by Poh et al.,[39] data are reported on overall patterns of reflux frequency and acid exposure in relation to recumbency before and after the first episode of stable sleep, and it is stated that ‘some’ reflux episodes occurred during sleep. In their other study, Poh et al. found that acid reflux was ‘associated’ with 54 of the 104 of these ‘conscious’ awakenings, with 14.4% of these reflux episodes occurring during sleep.[38] However, this conclusion is likely to be overstated, because the ‘duration of reflux’ was defined as the time that oesophageal pH was below 4 (an analysis approach that does not evaluate sleep state at the time of reflux onset) and because actigraphy cannot be used to document the timings of intervals of stable sleep reliably.

Mechanistic studies of sleep and reflux using polysomnography

The use of polysomnography presents significant practical problems for mechanistic research because it is a cumbersome, relatively expensive and intrusive recording method. However, it remains the current ‘gold standard’ with which to assess sleep comprehensively and is, therefore, the most accurate method for correlating sleep state with reflux. Our searches identified 15 mechanistic studies that used this method (Table 1).[2, 21, 24, 27-37, 40]

Overall comparisons of sleep architecture in patients with reflux disease vs. healthy volunteers

There is a notable lack of within-study polysomnographic comparisons of detailed sleep architecture between patients with reflux disease and healthy volunteers, presumably because of the significant challenges of such a study and the complexity of this recording method.

Epoch-based analyses of polysomnographic recordings and reflux episodes

We identified 13 studies that relied primarily or solely on epoch-based sleep analyses of polysomnographic recordings.[2, 27-37, 40] With this approach, these studies found that 13–75% of sleep period reflux episodes occurred during actual sleep in healthy individuals, patients with sleep disorders and those with reflux disease (Table 1).

Four of the 13 primarily epoch-based studies supplemented their analysis with a second-by-second scoring of arousals/awakenings around the time of onset of reflux episodes,[28, 29, 34, 36] but incomplete or temporally imprecise data were reported for these secondary analyses. For reflux episodes scored as occurring during sleep on the basis of epochal analysis, 68–99% were reported as being ‘associated’ (defined variably) with arousals or awakenings. The illustration of both epoch-based and second-by-second sleep analyses around a sleep period reflux episode from Kuribayashi et al.[34] (Figure 4) reveals the inadequacies of assessing sleep state at the time of onset of reflux using an epoch-based approach.

Apart from the study by Orr et al.,[33] the primarily epoch-based studies evaluated relatively small numbers of individuals. Results from participants both with and without GERD are reported. Some studies included individuals with or without subjectively assessed sleep disturbance or with obstructive sleep apnoea (OSA), with or without GERD. In several of these studies, a close ‘association’ (defined variably – see Table 1) was noted between epochs of wakefulness and reflux episodes, but this was usually interpreted as evidence that the wakefulness was caused by the reflux.

Second-by-second analyses of polysomnographic recordings and reflux

Healthy individuals

Only one study of healthy volunteers was identified in which polysomnographic recordings around the time of reflux onset were systematically analysed.[21] Over two consecutive nights (each ‘night’ being a 12-h period encompassing an evening meal, an awake postprandial period and a sleep period of about 8 h), 272 reflux episodes were recorded in 10 individuals. Data on reflux onset and sleep state were confined to the second study night because polysomnography was only conducted on that night. A detailed numerical analysis of the sleep/awake state at the onsets of the approximately 130 acid reflux episodes recorded during sleep monitoring on the second night is not provided in that report, but the results section states that the onset of acid reflux occurred ‘only during arousals or more prolonged periods of wakefulness’. Figure 2 illustrates one of the reflux episodes recorded in this study during polysomnography.

Patients with reflux disease

Freidin et al. concluded from their study of 11 patients with GERD that wakefulness or arousals were necessary conditions for reflux to occur during the sleep period.[24] An initial epochal analysis found that 92 of the 105 reflux episodes had their onset during wakefulness and 13 during sleep. The polysomnography recordings for the 10 episodes scored as occurring during stage II NREM sleep were re-examined on a second-by-second basis, revealing that in all cases, reflux onset took place during brief arousals that were not recognised by the 60-s epoch scoring approach. No re-examination of the other three episodes scored as occurring during other stages of sleep was mentioned.

Due to the relatively small sample of 11 patients with reflux oesophagitis in the study by Freidin et al.,[24] it was not possible to evaluate sleep state/reflux relationships according to clinically important subgroups of patients with different mixes of pathophysiological causes of GERD.[58] Although Freidin et al. did not describe the spectrum of severity of reflux oesophagitis in their patients with reflux disease,[24] it is likely that few would have had severe reflux oesophagitis and the associated very high levels of sleep period reflux.[49, 51] Patients with LA grade C or D reflux oesophagitis typically have large hiatus hernias, extreme laxity of the diaphragmatic crura and a particularly low basal LOS pressure.[58] Such patients are most at risk of occurrence of reflux during stable sleep and hence should be studied as a separate group.

Patients with snoring and/or OSA – reflux disease status unknown

Penzel et al. used a mixture of epoch-based sleep analysis and second-by-second scoring of arousals for correlating sleep with reflux in 15 patients with OSA and/or snoring problems, but the data reported did not include a second-by-second correlation of arousals or awakenings with reflux onset.[29] Their report is, however, of particular interest as they provide an illustration of a polysomnographic and pH tracing during an atypically gradual onset of apparent oesophageal acidification that occurred during clearly documented stable sleep (Figure 5). There are two possible explanations for this event. First, the apparent oesophageal acidification could be a recording artefact due to downwards displacement of the pH electrode into the stomach, suggested by the unusual time pattern of the pH decrease, or secondly, it could be a true reflux event with mechanics different from those of the great majority of reflux episodes. This was the only episode of apparent oesophageal acidification that Penzel et al. found to occur without ‘associated’ arousal or awakening out of a total of 69 reflux episodes.[29] If this was a true reflux episode, to our knowledge, it is the only one that has been clearly documented to occur in an adult during stable sleep. It remains unclear whether this individual had GERD.

image

Figure 5. Recording of the single published instance of reflux that had its onset during clearly demonstrated stable sleep, in this case associated with snoring. The polysomnography recording in the upper three panels shows no sign of arousal or awakening. Oesophageal acidification has an atypically gradual evolution compared with the abrupt acidifications seen in most sleep period reflux episodes (see Figures 2 and 4). Adapted from Penzel et al.[29] with permission. EEG, electroencephalogram; EMG: electromyogram; EOG, electro-oculogram; Flow, oronasal airflow; pH, oesophageal pH; SaO2, arterial oxygen saturation.

Download figure to PowerPoint

Mechanical function of the gastro-oesophageal junction associated with the onset of reflux in the sleep period

Six studies investigated the mechanical factors underlying the abrupt occurrence of reflux during the sleep period.[21, 24, 28, 34-36] In this regard, the patterns of motor activity of the LOS and diaphragm are crucial measures. To date, there has been little emphasis on distinguishing diaphragmatic function from that of the LOS in studies during the sleep period. The study by Kuribayashi et al.[35] is the only one that has been identified as commenting on diaphragmatic function during sleep period reflux. These authors reported that transient LOS relaxations associated with OSA were associated with manometric patterns consistent with potent crural diaphragmatic inhibition; no such inhibition was seen for apnoeic episodes occurring independently of transient relaxations.[35] This illustrates the possibility that the diaphragmatic inhibitory component of transient LOS relaxations[58] could play a mechanical role in sleep period reflux.

LOS function during sleep period reflux episodes

Six studies used pH or pH/impedance monitoring with oesophageal manometry to evaluate motor patterns at the time of sleep period reflux.[21, 24, 28, 34-36] Transient LOS relaxations were judged to account for 40–100% of sleep period reflux episodes in healthy individuals or patients with OSA.[21, 28, 34-36] Similarly, in studies of patients with reflux disease, it was concluded that 40–100% of reflux episodes were related to transient LOS relaxations.[24, 34, 35]

The motor patterns other than transient relaxation reported to be associated with reflux included ‘stress reflux’, ‘free reflux’ and ‘unclear mechanism’. The wide range of estimates of episodes attributable to transient LOS relaxations suggests that there was a problem with recognition of transient relaxation in some of these studies. The problem of accurate scoring of transient LOS relaxations is outside the scope of this review, but a discussion of this issue suggests that in studies finding relatively low proportions of episodes attributable to transient LOS relaxations, there is a significant miss rate for this pattern of LOS function.[58]

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion – part I: overall patterning of sleep period reflux and oesophageal acid clearance
  6. Results and discussion – part II: sleep state and antireflux function at the time of reflux
  7. Conclusions
  8. Authorship
  9. Acknowledgements
  10. References

There is a deeply embedded belief that a major, even overwhelming, part of sleep period reflux occurs during stable sleep. This concept is strongly linked to the view that the impairment of sleep associated with GERD arises primarily from premature awakenings caused by intrusive sensations generated by the occurrence of reflux during otherwise stable sleep. The data evaluated in this review suggest that these are over-simple interpretations of the sequence of events underlying nocturnal reflux in GERD and its associated sleep disturbances. Of the papers assessed in this review, the two studies that carried out temporally precise analyses in healthy individuals and patients with reflux disease together evaluated 232 episodes of reflux: not one of these had their onset during documented sleep.[21, 24] A third paper,[29] which did not report adequate information on a systematic second-by-second analysis, illustrates a tracing of a single instance of an episode of apparent reflux (that could be real or a recording artefact) that started during documented stable sleep. Although this suggests that reflux can occur during stable sleep, its apparent rarity supports the main alternative scenario that the great burden of sleep-time reflux episodes occurs during arousals or awakenings. The main cause of reflux-induced sleep impairment is likely to be long periods of nocturnal oesophageal exposure to noxious gastric fluid. It is also likely that the majority of these episodes are caused by prolonged failure of oesophageal clearance of reflux that occurred during arousals/awakenings because of early resumption of stable sleep.

It is surprising that there has been so little research on the mechanisms that underlie the occurrence of reflux episodes in patients with reflux disease during the sleep period, their relationship with sleep state and the factors that determine whether a sleep period reflux episode leads to symptoms and/or sleep disruption. The still significant technical challenge of such studies has recently been reduced by the development of solid-state, high-resolution manometry, combined with pH and impedance monitoring. Results from the studies of Kuribayashi and colleagues demonstrate the power of these recording methods for the study of sleep period oesophageal function.[28, 35]

This review highlights the need for the use of polysomnography to assess sleep for mechanistic studies of sleep and reflux. The key to gaining further mechanistic insights is wide adoption of second-by-second mapping of sleep/arousals/awakenings around the time of onset of reflux.

Authorship

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion – part I: overall patterning of sleep period reflux and oesophageal acid clearance
  6. Results and discussion – part II: sleep state and antireflux function at the time of reflux
  7. Conclusions
  8. Authorship
  9. Acknowledgements
  10. References

Guarantor of the article: J. Dent.

Author contributions: JD conceived the review, analysed the data, wrote preallocated sections of the manuscript and commented on the entire manuscript. RH analysed the data, wrote preallocated sections of the manuscript and commented on the entire manuscript. PE analysed the data, wrote preallocated sections of the entire manuscript and commented on the manuscript. All authors have approved the final version of the manuscript.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion – part I: overall patterning of sleep period reflux and oesophageal acid clearance
  6. Results and discussion – part II: sleep state and antireflux function at the time of reflux
  7. Conclusions
  8. Authorship
  9. Acknowledgements
  10. References

Declaration of personal interests: None.

Declaration of funding interests: Dr Anja Becher, from Oxford PharmaGenesis™ Ltd, provided writing support funded by AstraZeneca R&D, Mölndal, Sweden. Peter Eastwood is supported by the Australian National Health and Medical Research Council (fellowship no. 513704).

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results and discussion – part I: overall patterning of sleep period reflux and oesophageal acid clearance
  6. Results and discussion – part II: sleep state and antireflux function at the time of reflux
  7. Conclusions
  8. Authorship
  9. Acknowledgements
  10. References
  • 1
    Shaker R, Castell DO, Schoenfeld PS, Spechler SJ. Nighttime heartburn is an under-appreciated clinical problem that impacts sleep and daytime function: the results of a Gallup survey conducted on behalf of the American Gastroenterological Association. Am J Gastroenterol 2003; 98: 148793.
    Direct Link:
  • 2
    Dickman R, Green C, Fass SS, et al. Relationships between sleep quality and pH monitoring findings in persons with gastroesophageal reflux disease. J Clin Sleep Med 2007; 3: 50513.
  • 3
    Gerson LB, Fass R. A systematic review of the definitions, prevalence, and response to treatment of nocturnal gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2009; 7: 3728.
  • 4
    Johnson D, Orr WC, Crawley JA, et al. Effect of esomeprazole on nighttime heartburn and sleep quality in patients with GERD: a randomized, placebo-controlled trial. Am J Gastroenterol 2005; 100: 191422.
    Direct Link:
  • 5
    Mathur R, Douglas NJ. Frequency of EEG arousals from nocturnal sleep in normal subjects. Sleep 1995; 18: 3303.
  • 6
    Bonnet MH, Arand DL. EEG arousal norms by age. J Clin Sleep Med 2007; 3: 2714.
  • 7
    Allen L, Poh CH, Gasiorowska A, et al. Increased oesophageal acid exposure at the beginning of the recumbent period is primarily a recumbent-awake phenomenon. Aliment Pharmacol Ther 2010; 32: 78794.
  • 8
    Ancoli-Israel S, Cole R, Alessi C, Chambers M, Moorcroft W, Pollak CP. The role of actigraphy in the study of sleep and circadian rhythms. Sleep 2003; 26: 34292.
  • 9
    Acebo C, LeBourgeois MK. Actigraphy. Respir Care Clin N Am 2006; 12: 2330, viii.
  • 10
    Rowe M, McCrae C, Campbell J, et al. Actigraphy in older adults: comparison of means and variability of three different aggregates of measurement. Behav Sleep Med 2008; 6: 12745.
  • 11
    Blackwell T, Redline S, Ancoli-Israel S, et al. Comparison of sleep parameters from actigraphy and polysomnography in older women: the SOF study. Sleep 2008; 31: 28391.
  • 12
    Blood ML, Sack RL, Percy DC, Pen JC. A comparison of sleep detection by wrist actigraphy, behavioral response, and polysomnography. Sleep 1997; 20: 38895.
  • 13
    de Souza L, Benedito-Silva AA, Pires ML, Poyares D, Tufik S, Calil HM. Further validation of actigraphy for sleep studies. Sleep 2003; 26: 815.
  • 14
    Kushida CA, Chang A, Gadkary C, Guilleminault C, Carrillo O, Dement WC. Comparison of actigraphic, polysomnographic, and subjective assessment of sleep parameters in sleep-disordered patients. Sleep Med 2001; 2: 38996.
  • 15
    Signal TL, Gale J, Gander PH. Sleep measurement in flight crew: comparing actigraphic and subjective estimates to polysomnography. Aviat Space Environ Med 2005; 76: 105863.
  • 16
    Sivertsen B, Omvik S, Havik OE, et al. A comparison of actigraphy and polysomnography in older adults treated for chronic primary insomnia. Sleep 2006; 29: 13538.
  • 17
    Paquet J, Kawinska A, Carrier J. Wake detection capacity of actigraphy during sleep. Sleep 2007; 30: 13629.
  • 18
    Iber C, Ancoli-Israel S, Chesson A, Quan SF. The AASM Manual for the Scoring of Sleep and Associated Events. Westchester, IL: American Academy of Sleep Medicine, 2007.
  • 19
    Younes M. Role of arousals in the pathogenesis of obstructive sleep apnea. Am J Respir Crit Care Med 2004; 169: 62333.
  • 20
    Younes M, Loewen AH, Ostrowski M, Laprairie J, Maturino F, Hanly PJ. Genioglossus activity available via non-arousal mechanisms vs. that required for opening the airway in obstructive apnea patients. J Appl Physiol 2012; 112: 24958.
  • 21
    Dent J, Dodds WJ, Friedman RH, et al. Mechanism of gastroesophageal reflux in recumbent asymptomatic human subjects. J Clin Invest 1980; 65: 25667.
  • 22
    Orr WC, Johnson LF, Robinson MG. Effect of sleep on swallowing, esophageal peristalsis, and acid clearance. Gastroenterology 1984; 86: 8149.
  • 23
    Orr WC, Robinson MG, Johnson LF. Acid clearance during sleep in the pathogenesis of reflux esophagitis. Dig Dis Sci 1981; 26: 4237.
  • 24
    Freidin N, Fisher MJ, Taylor W, et al. Sleep and nocturnal acid reflux in normal subjects and patients with reflux oesophagitis. Gut 1991; 32: 12759.
  • 25
    Dodds WJ, Kahrilas PJ, Dent J, Hogan WJ, Kern MK, Arndorfer RC. Analysis of spontaneous gastroesophageal reflux and esophageal acid clearance in patients with reflux esophagitis. Neurogastroenterol Motil 1990; 2: 7989.
  • 26
    Orr WC, Johnson LF. Responses to different levels of esophageal acidification during waking and sleep. Dig Dis Sci 1998; 43: 2415.
  • 27
    DiMarino AJ Jr, Banwait KS, Eschinger E, et al. The effect of gastro-oesophageal reflux and omeprazole on key sleep parameters. Aliment Pharmacol Ther 2005; 22: 3259.
  • 28
    Kuribayashi S, Massey BT, Hafeezullah M, et al. Terminating motor events for TLESR are influenced by the presence and distribution of refluxate. Am J Physiol Gastrointest Liver Physiol 2009; 297: G715.
  • 29
    Penzel T, Becker HF, Brandenburg U, Labunski T, Pankow W, Peter JH. Arousal in patients with gastro-oesophageal reflux and sleep apnoea. Eur Respir J 1999; 14: 126670.
  • 30
    Ing AJ, Ngu MC, Breslin AB. Obstructive sleep apnea and gastroesophageal reflux. Am J Med 2000; 108 (Suppl. 4a): 120S5S.
  • 31
    Cohen JA, Arain A, Harris PA, et al. Surgical trial investigating nocturnal gastroesophageal reflux and sleep (STINGERS). Surg Endosc 2003; 17: 394400.
  • 32
    Suzuki M, Saigusa H, Kurogi R, et al. Arousals in obstructive sleep apnea patients with laryngopharyngeal and gastroesophageal reflux. Sleep Med 2010; 11: 35660.
  • 33
    Orr WC, Goodrich S, Fernstrom P, Hasselgren G. Occurrence of nighttime gastroesophageal reflux in disturbed and normal sleepers. Clin Gastroenterol Hepatol 2008; 6: 1099104.
  • 34
    Kuribayashi S, Kusano M, Kawamura O, et al. Mechanism of gastroesophageal reflux in patients with obstructive sleep apnea syndrome. Neurogastroenterol Motil 2010; 22: 611e172.
  • 35
    Kuribayashi S, Massey BT, Hafeezullah M, et al. Upper esophageal sphincter and gastroesophageal junction pressure changes act to prevent gastroesophageal and esophagopharyngeal reflux during apneic episodes in patients with obstructive sleep apnea. Chest 2010; 137: 76976.
  • 36
    Shepherd K, Hillman D, Holloway R, Eastwood P. Mechanisms of nocturnal gastroesophageal reflux events in obstructive sleep apnea. Sleep Breath 2011; 15: 56170.
  • 37
    Mello-Fujita L, Roizenblat S, Frison CR, et al. Gastroesophageal reflux episodes in asthmatic patients and their temporal relation with sleep architecture. Braz J Med Biol Res 2008; 41: 1528.
  • 38
    Poh CH, Allen L, Gasiorowska A, et al. Conscious awakenings are commonly associated with acid reflux events in patients with gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2010; 8: 8517.
  • 39
    Poh CH, Gasiorowska A, Allen L, et al. Reassessment of the principal characteristics of gastroesophageal reflux during the recumbent period using integrated actigraphy-acquired information. Am J Gastroenterol 2010; 105: 102431.
  • 40
    Gagliardi GS, Shah AP, Goldstein M, et al. Effect of zolpidem on the sleep arousal response to nocturnal esophageal acid exposure. Clin Gastroenterol Hepatol 2009; 7: 94852.
  • 41
    Freidin N, Mittal RK, McCallum RW. Does body posture affect the incidence and mechanism of gastro-oesophageal reflux? Gut 1991; 32: 1336.
  • 42
    Ireland AC, Dent J, Holloway RH. Preservation of postural control of transient lower oesophageal sphincter relaxations in patients with reflux oesophagitis. Gut 1999; 44: 3136.
  • 43
    Sifrim D, Castell D, Dent J, Kahrilas PJ. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut 2004; 53: 102431.
  • 44
    Fornari F, Blondeau K, Mertens V, Tack J, Sifrim D. Nocturnal gastroesophageal reflux revisited by impedance-pH monitoring. J Neurogastroenterol Motil 2011; 17: 14857.
  • 45
    Schindlbeck NE, Heinrich C, Konig A, Dendorfer A, Pace F, Muller-Lissner SA. Optimal thresholds, sensitivity, and specificity of long-term pH-metry for the detection of gastroesophageal reflux disease. Gastroenterology 1987; 93: 8590.
  • 46
    Dickman R, Parthasarathy S, Malagon IB, et al. Comparisons of the distribution of oesophageal acid exposure throughout the sleep period among the different gastro-oesophageal reflux disease groups. Aliment Pharmacol Ther 2007; 26: 418.
  • 47
    Gudmundsson K, Johnsson F, Joelsson B. The time pattern of gastroesophageal reflux. Scand J Gastroenterol 1988; 23: 759.
  • 48
    Orr WC, Allen ML, Robinson M. The pattern of nocturnal and diurnal esophageal acid exposure in the pathogenesis of erosive mucosal damage. Am J Gastroenterol 1994; 89: 50912.
  • 49
    Adachi K, Fujishiro H, Katsube T, et al. Predominant nocturnal acid reflux in patients with Los Angeles grade C and D reflux esophagitis. J Gastroenterol Hepatol 2001; 16: 11916.
  • 50
    Champion G, Richter JE, Vaezi MF, Singh S, Alexander R. Duodenogastroesophageal reflux: relationship to pH and importance in Barrett's esophagus. Gastroenterology 1994; 107: 74754.
  • 51
    Masclee AA, de Best AC, de Graaf R, Cluysenaer OJ, Jansen JB. Ambulatory 24-hour pH-metry in the diagnosis of gastroesophageal reflux disease. Determination of criteria and relation to endoscopy. Scand J Gastroenterol 1990; 25: 22530.
  • 52
    Schoeman MN, Holloway RH. Integrity and characteristics of secondary oesophageal peristalsis in patients with gastro-oesophageal reflux disease. Gut 1995; 36: 499504.
  • 53
    Kaltenbach T, Crockett S, Gerson LB. Are lifestyle measures effective in patients with gastroesophageal reflux disease? An evidence-based approach. Arch Intern Med 2006; 166: 96571.
  • 54
    Harvey RF, Gordon PC, Hadley N, et al. Effects of sleeping with the bed-head raised and of ranitidine in patients with severe peptic oesophagitis. Lancet 1987; 2: 12003.
  • 55
    Bredenoord AJ, Weusten BL, Curvers WL, Timmer R, Smout AJ. Determinants of perception of heartburn and regurgitation. Gut 2006; 55: 3138.
  • 56
    Bonnet MH. Memory for events occurring during arousal from sleep. Psychophysiology 1983; 20: 817.
  • 57
    Öhrström E, Skanberg A. Longitudinal surveys on effects of road traffic noise: substudy on sleep assessed by wrist actigraphs and sleep logs. J Sound Vib 2004; 272: 1097109.
  • 58
    Dent J. Pathogenesis of gastro-oesophageal reflux disease and novel options for its therapy. Neurogastroenterol Motil 2008; 20(Suppl. 1): 91102.