Gastroesophageal reflux (GER) is frequent in infants, as evidenced by its main symptom, regurgitation; a highly prevalent self-limiting symptom in infants that is associated with physiologic maturation (1). Harmful consequences of GER, diagnosed as GER disease (GERD), may be associated with obstructive apnea, recurrent aspiration, feeding difficulties, failure to thrive, stridor, and wheezing (2). Because of the high prevalence of regurgitation and severity of potential complications in infants, GER and GERD are among the leading causes of referral to pediatric gastroenterologists.
Although crying, fussiness, and nocturnal irritability have all been associated with GERD in infants, little is known regarding the effect of GER on sleep quality in infants (3). Infants are unique in that they are in the process of developing a mature sleep-wake cycle; a process is influenced by several cultural and physiologic factors (4). Indeed, sleep problems are reported by nearly one-third of all parents (of infants) during the first year of life, with a proportion remaining unchanged as they become older children (5,6) Furthermore, recent reports have failed to demonstrate any relation between crying or irritability and GERD (7,8).
In adults, awakenings caused by GER are frequently related to acid GER episodes (AGER) because awakenings are triggered by painful stimuli (9). AGER has also been associated with arousals in young infants (10). Nonacid GER (NAGER), however, plays a major role in this age group because feedings are more frequent and postprandial periods are proportionally greater, with more reflux episodes containing partially buffered gastric contents (11). NAGER can only be detected and subsequently prove to be related to symptoms using multichannel intraluminal impedance-esophageal pH monitoring (MII-pH), which allows assessment of esophageal exposure to bolus, independent of its pH. To our knowledge, there have been no reports of studies using MII-pH to evaluate the role of GER in infants with poor sleep quality. In the present study, we report findings on 24 infants who underwent clinically indicated simultaneous polysomnography (PSG) and MII-pH. Our aim was to retrospectively evaluate the relation between GER (both AGER and NAGER) and the quality of sleep in infants.
We retrospectively evaluated 24 infants referred for MII-pH with a simultaneous sleep study during September 2008 through March 2010. The study protocol was approved by the institutional review board at Nationwide Children's Hospital. Exclusion criteria were previous antireflux surgery (fundoplication) and MII-pH studies that were <20 hours.
Studies were performed in the Sleep Laboratory at Nationwide Children's Hospital with simultaneous MII-pH and with no sedation or sleep deprivation. The MII-pH study lasted for approximately 24 hours, and the PSG was recorded for 7 to 10 hours during the MII-pH study. Electrodes were applied for electroencephalograms (C4/A1, O2/A1), electro-oculogram, submental electromyogram (EMG), tibialis anterior EMG, and electrocardiogram. Respitrace bands were placed across the thorax and the abdomen to measure chest and abdominal wall motion. A nasal pressure transducer, oronasal thermistor, and end-tidal PCO2 cannula were used to detect airflow, and a Massimo pulse oximeter was attached to a finger to continuously measure blood oxygen saturation (SaO2). During the PSG, patients were continuously recorded using an infrared video camera and observed by a PSG technician who recorded the events of interest. Data were recorded continuously on a Grass Technologies (Warwick, RI) computerized PSG system for 7 to 10 hours, with all data being synchronized using a Smart meter. There were no eating restrictions before each examination. Changes in sleep position as well as meal composition and timing were recorded in a log book.
Rapid eye movement (REM) sleep was defined by rapid and random ocular movements. Non-REM sleep was scored in 3 stages: stage 1 (no sleep spindles, K complexes, or slow wave activity), stage 2 (with either K complexes or sleep spindles and <20% slow wave activity), and stage 3 (>20% of the epoch contains 0.5–2 Hz, 75 μV, or greater activity). Arousals were scored during sleep when there was an abrupt shift in electroencephalography frequency (including alpha and theta) and/or the frequencies exceeded 16 Hz (but not spindles) and lasted at least 3 seconds, with at least 10 seconds of stable sleep preceding the change (12,13). Scoring of arousal during REM required a concurrent increase in submental EMG lasting at least 1 second.
The following definitions were used for analysis of sleep study:
1. Apnea/hypopnea index: number of apneas (central and obstructive) and hypopneas per hour of sleep.
2. Arousal index: number of arousals per hour of sleep.
3. Central apneas: absence of chest/abdominal wall motion and airflow for ≥2 breaths.
4. Desaturation: drop of >3% from baseline oxygen saturation.
5. Hypopneas: reduction in airflow ≥50%, in the presence of chest/abdominal wall motion, associated with SaO2 desaturation ≥3%, arousal, or awakening.
6. Obstructive apneas: chest/abdominal wall motion with absence or reduction by 90% of airflow for ≥2 breaths.
7. Sleep efficiency: time spent asleep (total sleep time) divided by the time period between lights off and lights on (total recording time).
8. Wakened after sleep onset (WASO): time spent awake after initial sleep onset and before the final awakening. SaO2 nadir and the percentage of sleep during which SaO2 was <90% were also tabulated.
The catheter was positioned so that the tip was above the lower esophageal sphincter by 13% of total distance between nostril and lower esophageal sphincter. Patients were allowed to have 1 meal (their regular diet) and this was recorded in a log book. Symptoms were registered in the impedance logger and in the log book. Symptoms included cough, stridor, drooling, choking, gagging, and vomiting.
The MII-pH catheter measures impedance (ohms) to electrical current between 2 sensors (channel), and it has 6 impedance channels and 1 (distal) pH sensor. Intragastric pH was not measured because it is not a standard of practice. A GER episode was defined by a fall in impedance to 50% of baseline occurring in the retrograde direction in 2 or more of the distal-most impedance channels. A GER episode was considered an AGER when the pH dropped and remained <4 for at least 5 seconds. An impedance-detectable reflux episode was considered a NAGER episode when the pH increased, remained unchanged, or decreased while remaining above pH 4.
AGER index was defined as abnormal when the distal esophageal pH was <4 for >12% of the study time. GER episodes were categorized according to the sleep stage during which each episode occurred. GER episodes were characterized by chemical content (acid/nonacid), duration of bolus contact time (BCT) (for impedance-detectable episodes), and total duration (BCT plus chemical clearance; for acid episodes). BCT was the period between the fall of impedance to <50% of baseline and the return to 50% of baseline. Chemical clearance was the period between the end of bolus exposure and the return of pH to 4. Other outcome variables included %NAGER exposure, the number of episodes per hour, and the mean acid clearance time during each period of the study (sleep, WASO, and daytime). Mean clearance time is the average duration of all AGER episodes.
Symptom Association Probabilities
Symptom association probabilities (SAPs) for awakenings and arousals were measured in 2-minute windows (intervals) beginning with the GER episode. SAP for respiratory events was measured in 5-minute windows, with the mid-point corresponding to the beginning of the reflux episode. To evaluate SAP, a contingency table was derived with cells corresponding to the presence and absence of an event and a GER episode, and a Fisher exact test was performed. The SAP was calculated by the formula ([1 − P value) × 100) and it was considered significant when ≥95%.
Numeric variables were described by their median and interquartile range, unless otherwise indicated. Categorical variables were described by their frequency. Frequencies were compared across groups with Pearson χ2 test (or Fisher exact test when indicated). GER parameters included reflux exposure (expressed as percentage of time), number of reflux episodes per hour, and mean clearance time (seconds). MII-pH parameters were compared according to the period (daytime, sleep time, and WASO) using the Friedman test. In all statistical tests, a P value of ≤0.05 was regarded as significant.
Nineteen of 24 patients (79.2%) presented with one or more significant morbidities (Table 1). Most patients (n = 17, 70.8%) were referred for studies aimed at investigating the relation between apnea events and GER, 6 (25%) to evaluate stridor, 2 (8.3%) to investigate noisy breathing during sleep, 1 patient for cyanotic spells, and 2 presented both apneas and stridor.
AGER Indices ranged from 0.3% to 60% (median 4.85%, IQR 1.65%–11.1%). Four patients (16.7%) presented abnormal AGER indices, 3 of whom were taking acid-suppressive medicines (1 taking a proton pump inhibitor and 2 taking a histamine-2 receptor antagonist). The use of acid-suppressive medicines did not influence AGER indices (median 5.3%, IQR 2%– 11.5% [on meds] vs median 3.65%, IQR 1.3%–9.2% [off meds], P = 0.64).
Across all patients, 331 reflux episodes occurred during sleep (range 1–47 per patient, median 12), 184 occurred during WASO (range 0–19 per patient, median 5.5), and 1606 occurred during daytime (range 25–144 per patient, median 63.5). The number of NAGER episodes per hour was significantly fewer during sleep (median 0.27, IQR 0.06–1.13) than during WASO (median 1.42, IQR 0.14–4.49) or daytime (range 1.85, IQR 0.61–2.6) (P < 0.01) (Table 2).
GER and Sleep Interruptions
Median sleep duration was 423.5 minutes (IQR 359–462.5), whereas median sleep efficiency was 71.6% (IQR 62.2%–81.6%). Sleep duration and sleep efficiency were not related to GER (data not shown). The number of arousals ranged from 7 to 86 (median 53), and arousal indices ranged from 2 to 14 (median 9). Fifty-six percent of NAGER episodes (47/84) and 36% of AGER episodes (89/247) preceded arousals (P = 0.001), but there were no differences in the proportion of AGER and NAGER episodes associated with arousals during individual stages of sleep (Table 3).
There were 165 arousals following reflux episodes (range 0–26, median 5); 60 following NAGER (range 0–14, median 1) vs 105 following AGER (range 0–20, median 2.5) (P = 0.1). Seven (29.2%) patients had a significant SAP for arousal, 6 of whom were receiving acid-suppression medication (P > 0.05); 5 of the 7 (71.4%) were because of NAGER, 1 was because of AGER (14.3%), and 1 with significant SAP for both AGER and NAGER (14.3%). Only one of these patients presented an abnormal AGER index (a patient with positive SAP because of NAGER). There were 43 arousals that preceded reflux episodes (median 1.5, range 0–8 per patient); these, however, were not significant for any patient.
The median number of awakenings per patient was 20.5 (range 10–53), with a median number of 3.68 awakenings occurring per hour (range 1.27–10.11). Across all patients, 13.8% of all awakenings (78/565) occurred within 2 minutes following a GER episode (26 following NAGER and 52 following AGER). The proportion of awakenings related to GER episodes ranged from 0% to 45.5% (median 10.5%) in each patient. SAP for awakenings was positive in 9 (37.5%) infants (7 receiving acid-suppression medications and 2 having abnormal AGER index). Four of the 9 infants had a positive SAP for awakenings because of AGER (1 who was off antireflux medications), 4 because of NAGER (only 1 who was off antireflux medications), and 1 because of both AGER and NAGER. Patients with awakenings related to GER presented longer mean clearance times of AGER during sleep (165.5 seconds [IQR 123.6–219.3] vs 92.8 seconds [IQR 30.1–133.9 ], P = 0.03, Fig. 1).
Two patients (8.3%) presented apnea, 2 presented (8.3%), and 12 (50%) presented both apnea and hypopnea, but only 1 patient presented a positive SAP. Only 1 patient presented an abnormal apnea hypopnea index because of central apneas; this patient was a male subject with Zellweger syndrome that presented normal acid exposure and whose apneas were not related to GER.
In the present study, we show that GER episodes are significantly associated with arousals and awakenings among infants and that NAGER plays a significant role in the association. Excessive night awakening is known to be related to AGER in both infants and older children, as well as in adulthood (3). Awakenings are thought to be an important protective mechanism because during sleep, there is no swallowing, and primary peristalsis during awakened periods after sleep onset could clear the esophagus (9). In adults, the most likely mechanism responsible for triggering GER-related arousals and awakenings is painful stimuli, which depends on more acidic GER as well as longer clearance times (14). For infants, in whom reflux would be expected to be predominantly NAGER, the mechanism(s) of arousal are unclear.
The frequent association of NAGER with arousals and awakenings described here is likely because of different mechanisms for symptom generation, as compared with AGER. Painful sensations in the esophagus are generated by mechanoreceptors, and by acid-sensitive sensors (chemoreceptors) (15). It has been shown that previous acid reflux episodes can sensitize the esophageal mucosa, enhancing perception of reflux episodes (14). Our data showed that acid clearance was longer in patients with positive SAP for awakenings, suggesting that prolonged acid exposure periods may possibly diminish the threshold for perception of pain stimuli, and thus necessitate the need for longer exposures to cause awakening.
The present study presents some important limitations. The time frame chosen for evaluating SAP for arousals and awakenings (2 minutes) may be too short and insensitive. Agrawal et al (16) reported that NAGER is associated with delayed symptom recognition by the patient after the beginning of the GER episode. Only 54% of heartburn associated with NAGER happened in the first 2 minutes after the episode (17). As a result, the association between arousals/awakenings and NAGER may have been underestimated. We chose 2 minutes because of the great frequency of arousals, and the fact that larger time frames could be associated with a greater proportion of arousals associated with GER episodes only by chance. Another important limitation is that a significant number of patients were using acid-suppressive drugs. More patients could have NAGER associated with sleep interruptions because AGER was under treatment. Moreover, some patients may have been successfully treated by those medications, and thus the proportion of patients with sleep interruptions to GER could be underestimated. Finally, the large number of patients with laryngotracheomalacia may have biased the results because this condition is associated with both poor sleep quality and GERD (18).
The sleep efficiency reported here was lower than that reported elsewhere in healthy young infants (71.6% vs 84% ± 8% at 3 months, 89% ± 6% at 6 months, and 90% ± 7% at 9 months) during home polygraphic studies (19); however, polysomnographic studies were not home based and sleep efficiency is significantly greater in infants (20). Also, there are no data on the effect of the impedance probe on sleep quality of infants. Therefore, we define a normal value for sleep efficiency in the present study because the catheter and the sleep study both interfere with sleep continuity in infants.
GER-associated apneas (17,21) were rare in the present study. We have previously reported that although 15.2% of apnea events are linked to GER episodes, the association is significant in only a small number of patients (12%) (21). In the study, only 1 patient presented GER-related apneas, and this patient did not present arousals or awakenings significantly related to GER. Therefore, we may conclude that the mechanisms behind GER-related apneas are different from those associated with sleep interruption.
The results of the study suggest that GER is an important cause of sleep interruptions and that NAGER plays an important role for infants. Possibly, nonpharmacological antireflux therapy should be the first line of treatment in infants with sleep interruption associated with GER. Although we did not have information on the usage of such measures in our patients during data collection, those measures may be effective against NAGER. The next step could include prokinetic drugs targeting the reduction of GER episodes, such as baclofen, although there is a lack of clinical trials evaluating this approach. Because the condition is generally self-resolving with time, surgical treatment should be rarely needed (20); however, Nissen fundoplication has been demonstrated to improve sleep quality in children with severe GERD, refractory to medical treatment (68%) (22).
Sleep-wake mechanisms during the first year of life are being developed at a fast pace, and there are several factors that may affect sleep quality in this age group. Clinical management of an infant with poor sleep quality poses a challenge for the pediatrician because sleep depends on the integrated functioning of several complex physiological processes. The study adds that GER episodes (both AGER and NAGER) interrupt the sleep in infants, even those without GERD, as determined by the absence of threshold distal esophageal acid exposure.
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