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Keywords:

  • acid gastro-oesophageal reflux;
  • multichannel intraluminal impedance-pH monitoring;
  • neonates;
  • sleep

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Financial interest
  10. Declaration of interest
  11. References

The aim of the present study was to investigate the impact of gastro-oesophageal acid reflux on sleep in neonates and, reciprocally, the influence of wakefulness (W) and sleep stages on the characteristics of the reflux (including the retrograde bolus migration of oesophageal acid contents). The pH and multichannel intraluminal impedance were measured during nocturnal polysomnography in 25 infants hospitalised for suspicion of gastro-oesophageal reflux. Two groups were constituted according to whether or not the infants displayed gastro-oesophageal reflux (i.e. a reflux group and a control group). There were no differences between the reflux and control groups in terms of sleep duration, sleep structure and sleep state change frequency. Vigilance states significantly influenced the gastro-oesophageal reflux pattern: the occurrence of gastro-oesophageal reflux episodes was greater during W (59 ± 32%) and active sleep (AS; 35 ± 30%) than during quiet sleep (QS; 6 ± 11%), whereas the mean duration of gastro-oesophageal reflux episodes was higher in QS than in W and AS. The percentage of retrograde bolus migrations of distal oesophageal acid content was significantly higher in AS (62 ± 26%) than in W (42 ± 26%) and QS (4.5 ± 9%). In neonates, gastro-oesophageal reflux occurred more frequently during W, whereas the physiological changes associated with sleep state increase the physiopathological impact of the gastro-oesophageal reflux. The duration of oesophagus–acid contact was greater during sleep; AS facilitated the retrograde migration of oesophageal acid content, and QS was characterised by the risk of prolonged acid mucosal contact.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Financial interest
  10. Declaration of interest
  11. References

Gastro-oesophageal reflux (GOR) is common in preterm and term neonates (Omari et al., 2002). When the condition causes symptoms or pathological complications (such as irritability, frequent vomiting, apnoea, aspiration pneumonia and failure to thrive), it is considered as gastro-oesophageal reflux disease (GORD). Increased acid exposure is a clinically relevant factor in GORD (Omari et al., 2002, 2005), and retrograde migration of gastric content into the mid- and proximal oesophagus can lead to aerodigestive complications (e.g. food aspiration, activation of laryngeal chemoreflexes, central and/or obstructive apnoeas, blood oxygen desaturation and bradycardia in sleeping infants; Krous et al., 2007; Menon et al., 1985; Thach, 2001). Moreover, current knowledge suggests that gastric reflux stimulates laryngeal chemoreflexes, which in turn leads to apnoea and bradycardia (Praud, 2010). Sleep has never been considered as a putative risk factor for migration of refluxed gastric content to the proximal oesophagus in infants, despite the fact that this relationship has been demonstrated in adults (Orr et al., 2000).

Despite a high frequency of reflux, the sporadic presence of respiratory problems and the great proportion of time spent asleep (60–80%) in neonates, there is very little information on the relationships between acid GOR, retrograde migration of acid oesophageal contents and sleep in infants. Paton et al. (1989) and Jeffery and Heacock (1991) performed short-duration sleep studies (lasting between 90 and 268 min, on average), but this duration may not have been sufficient to take into account variations in acid exposure (Vandenplas and Hegar, 2000). In addition, none of these studies measured the migration of acid GOR or the relationship between vigilance states and oesophageal acid exposure time. In adults, the results of Orr (2009) strongly suggested that the sleep-related acid contact time is a critical factor in the pathogenesis of complications of GOR in adults.

Although sleep integrity is of paramount importance in neurobehavioural development, body growth and physiological regulation in neonates (Curzi-Dascalova and Challamel, 2000; Mirmiran and Ariagno, 2003), we are only aware of two studies (Harris et al., 2003; Sondheimer and Hoddes, 1991) that have investigated the impact of GOR (as assessed by pH-metry) on sleep. However, both studies were performed in older infants (3–35 months old) in a context of respiratory disorders. Sondheimer and Hoddes (1991) did not observe sleep pattern differences when comparing infants with and without pathological levels of GOR. In contrast, Harris et al. (2003) described that the presence of severe GOR (pH < 4 during more than 10% of time) disturbed the sleep structure in infants by increasing the percentage of active sleep (AS). Moreover, other important sleep parameters (sleep efficiency, sleep time, sleep onset and the frequency of sleep stage changes) were not reported.

The shortcomings of the above-mentioned studies highlight the lack of comprehensive information on the relationship between acid GOR and sleep in infants. The goal of this study was to analyse the impact of acid GOR on sleep in neonates and, reciprocally, the influence of wakefulness (W) and sleep stages on the characteristics of acid reflux, including retrograde bolus migration of acid content investigated by multichannel intraluminal impedance (MII)-pH monitoring.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Financial interest
  10. Declaration of interest
  11. References

Subjects

Twenty-five neonates (mean ± SD, gestational age: 35.8 ± 4.6 weeks, postmenstrual age: 40.6 ± 3.5 weeks) hospitalised in the Paediatric Department at Amiens University Hospital (France) were evaluated for suspected GOR. The infants had been referred for overnight oesophageal monitoring by their attending physician because of recurrent regurgitation potentially caused by GOR. All newborn infants were free of severe diseases (neurological, infectious, cardiopulmonary and gastrointestinal diseases), and no medication was administered before and during the investigation. All infants were bottle-fed every 3–4 h with their usual formula. The parents had been informed of the protocol and had given their written consent. The protocol was approved by the Picardy Regional Independent Ethics Committee. Two groups were constituted, according to whether the infants showed GOR with oesophageal pH < 4 (the GOR group) or not (the control group).

Polysomnography (PSG)

Overnight PSG recording was started at 19:00 hours (i.e. after the last feed) and continued until the final awakening at 07:00 hours on Day 2. The overall duration of the recording was about 12 h. The clothed newborns slept in the supine position in a crib in a room isolated from routine nursing activities, noise and changes in light levels. The room temperature was maintained at 20 °C.

Polysomnography (using the Brainnet-Morpheus 3.75 system from Medatec®, Brussels, Belgium) included two electroencephalograms (EEGs) from the right and left centro-occipital leads, two electro-oculograms, an electrocardiogram and a body movement recording via actimeters attached to the wrist and (on the opposite body side) the ankle. Night-time video recording was used throughout the 12-h period. Time periods with nursing interventions and feeding episodes were excluded from the sleep and GOR analyses.

Sleep stages were scored visually in 30-s epochs, as recommended by Curzi-Dascalova and Mirmiran (1996). AS was defined as continuous EEG activity with rapid eye movements (REM), and quiet sleep (QS) was defined as discontinuous EEG activity in the absence of REM. Periods that did not fulfil the criteria for either AS or QS were scored as indeterminate sleep (IS). W was defined as a state in which the infant’s eyes were open and body movements were frequent. Crying or fussing was sometimes observed. For each infant, we calculated the sleep period time (SPT; from the first sleep onset to the last awakening), the percentage and frequency of W (expressed as a proportion of SPT), total sleep time (TST; defined as the difference between SPT and W durations), and the percentage and frequency of the different sleep stages (expressed as a proportion of TST). Sleep efficiency was defined as the ratio between TST and SPT.

MII-pH monitoring

All infants underwent MII-pH monitoring (MMS®, Enschede, Holland). Oesophageal pH was monitored as recommended by the ESPGHAN (Vandenplas, 2000). The system included a portable data logger with impedance-pH amplifiers and ion-selective field effect transistors and an impedance-pH catheter (outer diameter: 2 mm; Unisensor, Attikon®, Switzerland) containing a pH-measuring electrode and six impedance sensors (4-mm cylindrical ring electrodes). Each pair of ring electrodes represented an impedance measuring segment and corresponded to one recording channel. The distance between each impedance sensor was 2 cm. The pH-measuring electrode was located within the distal impedance recording channel, 1 cm from the probe’s distal tip. Before each experiment, the pH electrode was calibrated with pH 4 and 7 buffer solutions. The MII-pH catheter was introduced into the oesophagus via the nose, positioned according to Strobel’s formula (Strobel et al., 1979) and X-ray controlled. The signals from the impedance and pH channels were sampled at 50 and 1 Hz, respectively, stored in the battery-powered data logger, and (at the end of the recording period) downloaded into a personal computer.

The MII-pH recordings were analysed with Database Software® (version 8.9a; MMS, Enschede, The Netherlands). Impedance and pH signals collected during feeding were not analysed.

Impedance tracings were checked for the characteristic pattern of retrograde acid bolus movements. Retrograde acid migration was scored if the oesophageal pH fell below four and was accompanied by a 50% fall in impedance that began in the distal channel and propagated to more proximal channels. An episode detected by the pH electrode only (pH ≤ 4) was classified as acid GOR, whereas an episode detected by MII only was classified as a retrograde bolus movement.

For each neonate, GOR characteristics were analysed during AS, QS and W. The following parameters were calculated: the reflux index (RI; defined as the percentage of total time spent with oesophageal pH < 4); the total number, frequency and mean duration of acid GOR episodes.

Statistical analysis

Statistics were computed using Statview software (version 5.0; SAS Institute, Cary, NC, USA). Inter-group differences (i.e. the GOR group versus the control group, C) in clinical data, sleep characteristics and gastro-oesophageal events were probed with non-parametric, unpaired Mann–Whitney U-tests.

The relationship between GOR and sleep parameters was tested with Pearson’s correlation coefficient. The influence of vigilance states on oesophageal acid reflux characteristics was tested in a one-way analysis of variance (anova). When F-values were significant, post hoc Fisher protected least significant difference tests were computed. The significance threshold was set to 0.05, and results with P < 0.10 are quoted when relevant. Values are given as means ± SD.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Financial interest
  10. Declaration of interest
  11. References

General characteristics

Of the 25 neonates investigated, seven did not show any oesophageal acid events and were included in the control group. The remaining 18 neonates constituted the GOR group because of the presence of GOR. Table 1 summarizes the clinical parameters for the two groups of neonates. The gestational ages were similar in the control group (27–40 weeks) and the GOR group (26–40 weeks). Except for higher bodyweight at the time of the study in the GOR group than in the control group, there were no significant differences between the two groups.

Table 1.   Clinical parameters for the two groups of infants
 Control groupGOR group
  1. Values are means ± SD. Between-group differences were analysed with a non-parametric test.

  2. GOR, gastro-oesophageal reflux.

  3. *P < 0.05.

Number of infantsn = 7n = 18
Gestational age (weeks)35.1 ± 5.136.2 ± 4.5
Postnatal age (days)27.7 ± 12.335.9 ± 28.2
Postmenstrual age (weeks)39.0 ± 3.941.3 ± 3.3
Birth weight (g)2300 ± 9512592 ± 927
Weight at the time of the study (g)2588 ± 7293370 ± 709*

The GOR group was characterised by an overall RI of 2.9 ± 3.7%, a GOR frequency of 1.3 ± 1.3 h−1, a mean GOR episode duration of 1.0 ± 0.46 min and a mean longest GOR episode duration of 4.6 ± 5.8 min.

Sleep characteristics

Table 2 displays the sleep parameters during the PSG investigation for the two groups. No inter-group differences in the sleep parameters (i.e. sleep duration, sleep structure and sleep stage change frequency) were found.

Table 2.   PSG data in the two groups
 Control groupGOR groupGroup effect
  1. Values are means ± SD.

  2. AS, active sleep; GOR, gastro-oesophageal reflux; IS, indeterminate sleep; NS, non-significant; QS, quiet sleep; SPT, sleep period time; TST, total sleep time; W, wakefulness.

Number of infantsn = 7n = 18 
SPT (min)740 ± 117683 ± 171NS
TST (min)559 ± 125487 ± 127
Sleep efficiency (%)75 ± 1172 ± 9
Sleep structure
 W (% of SPT)24.8 ± 11.027.0 ± 10.0NS
 AS (% of TST)58.4 ± 10.063.8 ± 9.7
 IS (% of TST)8.4 ± 6.97.2 ± 4.7
 QS (% of TST)33.1 ± 7.829.7 ± 8.6
Mean episode duration (min)
 W9.8 ± 3.513.4 ± 8NS
 AS12 ± 4.713.5 ± 5.4
 IS3.1 ± 2.22.8 ± 1.1
 QS13.2 ± 4.212.9 ± 3.7
Frequency of sleep stage changes (min−1)0.11 ± 0.040.10 ± 0.02NS

In the GOR group, the frequency of sleep state changes was positively correlated (r = 0.60, P = 0.007) with the frequency of GOR.

GOR and vigilance states

In the GOR group, a total of 239 GOR episodes were detected during the recording. Vigilance states influenced the distribution of oesophageal acid episodes (F2,45 = 16.7; P < 0.001): the mean number of acid GOR episodes was higher during W (59 ± 32%) than during AS (35 ± 30%) and QS (6 ± 11%), although only the comparison with QS was statistically significant (Table 3).

Table 3.   pH monitoring data in the GOR group (239 GOR episodes) as a function of the vigilance state
 WASQSVigilance state effect
  1. Values are given as means ± SD.

  2. AS, active sleep; GOR, gastro-oesophageal reflux; NS, non-significant difference; QS, quiet sleep; W, wakefulness.

  3. indP < 0.10; *P < 0.05; **P < 0.001.

Duration (min)186 ± 88310 ± 98143 ± 46
Percentage of GOR episodes (%)59 ± 3235 ± 306 ± 11**AS versus QS **QS versus W
Total duration of GOR (min)4.9 ± 5.95.9 ± 8.54.8 ± 10.8NS
Proportion of time spent with GOR (%)2.7 ± 2.91.9 ± 2.72.8 ± 6.2
Frequency of GOR episodes (h−1)1.9 ± 1.81.1 ± 1.20.7 ± 1.2*W versus QS indW versus AS

The frequency of occurrence of acid GOR episodes was also influenced by the vigilance state (F2,51 = 3.7; P = 0.032), and was higher in W than in AS (P = 0.060) and QS (W versus QS: P = 0.011). In terms of the mean duration of acid episodes, the influence of vigilance states (F2,27 = 7.4; P = 0.003) resulted in a greater mean acid episode duration in QS than in W (P < 0.001) and AS (P = 0.002; Fig. 1). Overall, the W, AS and QS stages did not differ in terms of the total duration (min) and the proportion (%) of time spent with gastro-oesophageal acid episodes.

image

Figure 1.  The mean duration of acid gastro-oesophageal reflux (GOR) episodes as a function of the vigilance state. Values are given as means ± SD. AS, active sleep; QS, quiet sleep; W, wakefulness. *P < 0.05; **P < 0.001.

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Retrograde migration of acidic oesophageal content

Retrograde migration was observed in 44 ± 29% of GOR episodes. Vigilance states influenced the migration of GOR (F2,27 = 8.2; P = 0.002): the percentage of GOR episodes with a retrograde bolus migration was significantly higher in AS (61.6 ± 25.9%) than in W (41.7 ± 25.5%) and QS (4.5 ± 9.0%). All inter-state differences were statistically significant (Fig. 2).

image

Figure 2.  Percentages of acid gastro-oesophageal reflux (GOR) resulting in migration to the more proximal impedance sensor during wakefulness (W), active (AS) and quiet sleep (QS). Values are given as means ± SD. *P < 0.05; **P < 0.001.

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Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Financial interest
  10. Declaration of interest
  11. References

Influence of GOR on sleep

In the present study, we did not observe any sleep parameter difference between the control and GOR groups. In the GOR group, the RI (which characterises the severity of GOR) may have not been high enough to induce sleep disturbances. The neonates with GOR in the present study would not be considered as suffering from GORD, as the pH-based RI did not exceed 10% (Vandenplas et al., 1991). Similarly, Harris et al. (2003) did not find any sleep disruption in 3-month-old infants with a RI < 5%, whereas the presence of severe GOR (pH < 4 for more than 10% of total time) was associated with a greater amount of AS. Moreover, in older infants (3–35 months old), Sondheimer and Hoddes (1991) did not find differences between the sleep patterns of infants with and without pathological GOR. Nevertheless, the frequency of GOR episodes was found to influence the continuity of sleep: the higher the GOR frequency, the higher the sleep stage change frequency. This indicates the presence of greater sleep instability when the frequency of GOR increases – probably due to the visceral sensory perception when oesophageal afferents are stimulated by acid exposure.

GOR characteristics with regard to the vigilance state

In the present study, vigilance states influenced the occurrence of acid GOR episodes: 59% of them occurred during W, 35% during AS and 6% during QS. This result confirms those reported by Walsh et al. (1981) and Paton et al. (1989) in infants, and Jeffery et al. (1980) in healthy babies for whom most of the acid gastro-oesophageal events also occurred during W. Transient lower oesophageal sphincter relaxation is the predominant mechanism for GOR in infants (Omari et al., 2002). Our findings support a possible central modulation of the neural control of lower oesophageal sphincter tone as a function of the vigilance state.

However, there are other possible explanations. Jeffery and Heacock (1991) showed that movements preceded 88% of reflux episodes; this phenomenon could explain the greater occurrence of reflux in W. Indeed, the frequency of body movements decreases from W to AS and from AS to QS. Movement also increases gastric pressure, which is one of the mechanisms associated with reflux. Another mechanism is related to primary peristalsis elicited by swallowing, which generates volume arrival in the stomach, inducing mechanical reflexes and reflux. Although we did not analyse swallowing in the present study, it is well known that neonates swallow more frequently during W than during AS. Swallowing is least frequent (and sometimes even absent) during QS (Jeffery et al., 2000).

In the present study, we found that the mean duration of reflux events was higher during QS than during AS and W. A number of factors that are critical for acid clearance (such as salivary production; Dawes et al., 1972; swallowing; Jeffery et al., 2000; and, probably, the arousal response to acid mucosal contact) are markedly depressed during QS. These sleep-related changes may lead to delayed oesophageal acid clearance and could explain the prolongation of reflux episodes (and thus an increase in the duration of acid mucosal contact) in QS. As a result, the proportion of time spent with GOR in this sleep stage was similar to that seen during W and AS. Harris et al. (2003) reported the same findings in groups of infants with non-pathological reflux (i.e. RI < 10%).

In the present study, the time spent with acid mucosal contact was greater during sleep (AS + QS = 10.7 min) than during W (4.9 min). When we examined the data presented by Harris et al. (2003) for their pathological GOR group (i.e. RI > 10%), we found that total time spent at pH < 4 was also higher during sleep than during W. This observation is of clinical relevance, as oesophageal mucosal damage has been clearly associated with acid contact time (Orr, 2010).

The influence of vigilance states on the retrograde migration of acid reflux

Proximal migration was observed in 44% of the pH-detected reflux episodes. Francavilla et al. (2010) found that 69% of the reflux reached proximal channels in 7-month-old infants, but did not consider vigilance states and did not distinguish between acid and non-acid reflux. One limitation refers to pH events missed by MII, with an ensuing impact on the interpretation of proximal migration. According to various studies, between 9 (Condino et al., 2006) and 42% (Di Fiore et al., 2009) of pH events are missed by the MII technique. The impedance technique’s inability to identify these events may be due to several factors, including technical artefacts, low bolus size (probably negligible, as a bolus as small as 0.1 cm3 can be detected), catheter design and/or scoring rules. Di Fiore et al. (2009) noted that the discrepancy between pH monitoring and MII monitoring is smaller in term infants than in preterm infants.

In the present study, there was a clear association between vigilance state and acid migration; in AS, the number of retrograde migrations was significantly higher (62%) than in W (42%) and QS (4.5%). AS (which represents about 65% of TST) can therefore be considered as a risk factor for retrograde bolus acid migration in newborns. In adults, Orr et al. (2000) found that proximal migration was significantly more likely during sleep: 73% of reflux events resulted in proximal migration during sleep, compared with only 26% of events during waking. Orr et al. (2000) suggested that acid clearance took longer during sleep. In our study, we did not observe any difference in reflux episode mean duration for W and AS, which suggests that prolongation of acid clearance phenomenon is not the main explanatory factor for the greater proximal migration observed in AS. Body movements and apnoeic episodes (which both occur more frequently during AS; Bach et al., 1994) may constitute another explanation. The increase in abdominal pressure that results from body movement may temporarily overwhelm the pressure barrier at the base of the oesophagus (usually characterised by lower distal pressure than in the mid- and proximal oesophagus). The subsequently induced pressure gradient could promote oesophageal migration. A relationship with obstructive apnoea may be related to a physical mechanism whereby negative intrathoracic pressure sucks gastric content into the oesophagus (Menon et al., 1985).

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Financial interest
  10. Declaration of interest
  11. References

Newborn infants spend 60–80% of their time asleep. An important finding was that sleep was not actually disrupted by GOR. Given that the present study’s results apply to infants without GORD, it is not known whether they apply to those suffering from GORD. To progress our understanding of the potentially harmful effect of GORD on sleep, it would be useful to analyse this relationship in infants with GORD and establish whether sleep disruption could be involved in the failure to thrive often observed in such a population.

In contrast, our data show that sleep-related physiological changes modify the characteristics of GOR. AS facilitates the oesophageal retrograde migration of GOR. The low number of GOR episodes in QS was nevertheless characterised by a greater risk of prolonged acid mucosal contact. Acid exposure time was higher during sleep than during W.

The occurrence of GOR and the retrograde migration of acid content to the proximal oesophagus increase the likelihood of gastric aspiration (Orenstein, 2001). Therefore, AS can be considered as a period of increased vulnerability; the reflexes that protect the airways against aspiration are depressed during this sleep state (Page and Jeffery, 2000). Moreover, some (controversial) data support a hypothesis in which pulmonary aspiration of gastric content during sleep is indirectly involved in the Sudden Infant Death Syndrome (SIDS) because of agonal respiratory efforts. Because gastric content is present in the lung of 14–40% of SIDS victims, gastric aspiration may be a terminal event that some infants (representing a subset of SIDS cases) cannot overcome (Krous et al., 2007).

Further work is also needed to identify and analyse all reflux episodes, regardless of the content (liquid, gas or mixed) and the latter’s pH (acidic, weakly acidic or non-acidic reflux). This would doubtless help to clarify the relationship between sleep and GOR in newborn infants.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Financial interest
  10. Declaration of interest
  11. References

This work was funded by the Picardy Regional Council. Mohammed Ammari received a postdoctoral grant from the Picardy Regional Council. We thank the staff of the Neonatology Department at Amiens University Hospital (Amiens, France) for assistance with the experiments. Our warm gratitude goes to Dr David Fraser for helpful advice on the manuscript’s English.

Declaration of interest

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Financial interest
  10. Declaration of interest
  11. References

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. Financial interest
  10. Declaration of interest
  11. References
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