Frederick W. Woodley

Testing the association between gastroesophageal reflux and apnea in infants.

Background: There is controversy regarding the association between gastroesophageal reflux and apnea. The controversy is further confused by the variety of ways reflux is detected, the varying methods of data analysis and the heterogeneity of subjects studied. Objectives: To determine if apnea is associated with reflux and to determine whether the association differs with acid or non acid reflux. Methods: We prospectively evaluated infants with apparent life-threatening events or apnea by simultaneous pneumography, esophageal pH and multichannel intraluminal impedance monitoring. Apneic events and reflux frequency, duration, acidity and height were recorded. Apneic events were considered to be temporally linked to gastroesophageal reflux when they occurred during a gastroesophageal reflux episode or within 5 minutes after clearance of the refluxate. Data described with frequency tables, scatterplots and time series graphs were analyzed by regression analysis and χ2 testing. Results: Twenty-five infants (10 males) aged 1 to 19 months were studied for up to 24 hours. Of 527 total apneic episodes, only 80 (15.2%) were temporally linked with gastroesophageal reflux: 37 (7.0%) with acid reflux and 43 (8.2%) with non-acid reflux. Scatterplots revealed no significant correlation between apnea and frequency or duration of reflux episodes. Individual χ2 analyses within subjects found limited associations between reflux and apnea. Regression analyses showed a significant association between apnea and reflux in 4 of 25 subjects. Conclusions: We found little evidence for an association between apnea and total reflux, acid reflux or non-acid reflux. There was no difference between acid gastroesophageal reflux and non-acid gastroesophageal reflux in the frequency association with apnea. Either a χ2 statistic for each subject or R2 value computed from a lagged regression model for each subject can be used as an index of association in patient evaluation.

Esophageal Impedance Monitoring for Gastroesophageal Reflux

Dual pH-multichannel intraluminal impedance (pH-MII) is a sensitive tool for evaluating overall gastroesophageal reflux disease, and particularly for permitting detection of nonacid reflux events. pH-MII technology is especially useful in the postprandial period or at other times when gastric contents are nonacidic. pH-MII was recently recognized by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition as being superior to pH monitoring alone for evaluation of the temporal relation between symptoms and gastroesophageal reflux. In children, pH-MII is useful to correlate symptoms with reflux (particularly nonacid reflux), to quantify reflux during tube feedings and the postprandial period, and to assess efficacy of antireflux therapy. This clinical review is simply an evidence-based overview addressing the indications, limitations, and recommended protocol for the clinical use of pH-MII in children.

Gastroesophageal Reflux in Cystic Fibrosis: Current Understandings of Mechanisms and Management

Cystic fibrosis (CF) is an inherited disease that affects both the lungs and the digestive system in children and adults. Thick mucus fills the gut and blocks lumens of the pancreas and hepatobiliary systems, creating insufficient pancreas function and liver disease. Chronic gastrointestinal (GI) complications, including intestinal obstruction, occur in neonates, and poor digestion and gastroesophageal reflux disease (GERD) in children. Although GI symptoms tend to improve with age, CF and associated GERD eventually create respiratory insufficiency; the only available treatment option at this stage is a bilateral lung transplant, which carries considerable morbidity and mortality. While GERD may reoccur as a complication of lung transplantation, GERD symptoms are often reduced following a fundoplication.

Gastroesophageal reflux causing sleep interruptions in infants.

Background and Aim: Little is known about the relation between gastroesophageal reflux (GER) episodes and sleep interruptions in infants. The aim of the study was to evaluate the relationship between GER and the incidence of sleep interruptions in infants. Methods: Study patients included 24 infants (younger than 1 year) referred for multichannel intraluminal impedance and esophageal pH monitoring with simultaneous polysomnography. Exclusion criteria were a previous fundoplication and studies lasting <20 hours. Tests were clinically indicated to investigate suspicion of GER-related apnea (17, 70.8%), stridor (6, 25%), noisy breathing (2, 8.3%), and cyanotic spells (1, 4.2%). Most patients presented with significant comorbidities (19, 79.2%). Results: The number of nonacid GER (NAGER) per hour was greater during sleep time than during daytime and awakening following sleep onset (median 0.27 vs 1.85 and 1.45, P < 0.01). A total of 1204 (range 7–86 per infant) arousals in 24 infants was detected, 165 (13.7%) that followed GER episodes, and 43 (3.6%) that preceded GER episodes. Seven patients presented with a positive symptom association probability for arousals; 5 were exclusively because of NAGER. A positive symptom association probability for awakenings was detected in 9 patients; 4 were because of NAGER, 4 were because of AGER, and 1 was because of both NAGER and GER. Patients with awakenings related to GER presented longer mean clearance time of AGER during sleep (165.5 vs 92.8 seconds, P = 0.03). Conclusions: GER was a frequent cause of interrupting sleep among our infant patients, and NAGER proved to be equally important as AGER for causing arousals and awakenings in infants.

Acid Gastroesophageal Reflux in Symptomatic Infants Is Primarily a Function of Classic 2-phase and ph-only Acid Reflux Event Types

Background: Combined esophageal pH monitoring (EPM) and multichannel intraluminal impedance (MII) reveal 4 unique acid gastroesophageal reflux (AGER) types in infants: classic 2-phase, single-phase, pH-only events (POEs), and re-reflux episodes. The extent to which different AGER event types contribute to AGER frequency, acid reflux exposure time (ARET), and the number of episodes lasting 5 minutes or longer, has never been reported. In this study, EPM/MII was used to assess AGER in symptomatic infants on the basis of these 4 AGER types. Materials and Methods: EPM/MII tracings from 12 symptomatic infants (<12 months old) were examined. Mean frequencies and durations of each AGER type, percentages of total ARET due to each AGER type, and percentages of different AGER types lasting 5 minutes or longer, were measured. Results: Of 926 total AGER events, 23.1%, 6.3%, 69.2%, and 1.5% were classic 2-phase, single-phase, POEs, and re-reflux episodes, respectively. In 20.2 hours of combined ARET, 52.3%, 2.3%, 42.4%, and 3.0% occurred during classic 2-phase, single-phase, POEs, and re-reflux episodes, respectively. Classic 2-phase and POE events were both more frequent than single-phase (P = 0.002 and P < 0.0001) and re-reflux (P = 0.002 and P < 0.0001) episodes, respectively. Increasing numbers of AGER episodes were strongly correlated with POEs (P = 0.0001). Of the 35 total AGER episodes that lasted 5 minutes or longer, 94% were classic 2-phase episodes or POEs (57% and 37%, respectively). Conclusions: In symptomatic infants, total AGER episodes, total ARET, and AGER episodes lasting 5 minutes or longer are largely a function of classic 2-phase and pH-only AGER types.

pH-only acid reflux events in infants during later phases of the feeding cycle are less acidic and cleared more efficiently than classic 2-phase acid reflux events.

Background: Gastroesophageal acid exposure in infants is a function of 4 acid gastroesophageal reflux (AGER) types: classic 2-phase, single-phase, and pH-only events (POEs), as well as rereflux episodes. In symptomatic infants, classic 2-phase events and POEs make up the majority of total AGER events and AGER events lasting 5 minutes or longer, and are responsible for the majority of total gastroesophageal acid exposure. Also, in symptomatic infants, chemical clearance efficiency of classic 2-phase events has been shown to be influenced by feeding. Pathogenicity of AGER involves variables that include frequency, duration, and pH of AGER events. The purpose of this investigation was to compare classic 2-phase episodes and POEs on the basis of these variables during discrete periods related to feeding. Patients and Methods: Impedance/pH tracings from 12 symptomatic infants (median age 20 weeks) were examined. Mean frequencies, durations, and nadir pH values were calculated during feeding, the first hour postprandial (1stPP), the second hour postprandial (2ndPP), and fasting. Results: Compared with classic 2-phase events, POEs were cleared significantly more efficiently during 1stPP (3-fold, P = 0.02), 2ndPP (3-fold, P = 0.0001), and fasting (4.5-fold, P < 0.0001), and were less acidic during 2ndPP (1.9 ± 0.15 vs 2.6 ± 0.07, P = 0.0005) and fasting (1.5 ± 0.12 vs 2.9 ± 0.07, P < 0.0001). Whereas clearance of classic 2-phase events became increasingly less efficient, clearance of POEs did not fluctuate significantly during the course of the feeding cycle. Conclusions: The lower acidity and more rapid clearance during 2ndPP and fasting suggest that POEs are likely to have a different clinical impact (compared with classic 2-phase AGER events) during later phases of the feeding cycle.

Chemical clearance in infants and children with Acid reflux in the physiologic range.

Background and Aim: We reported that chemical clearance (CC) of acid gastroesophageal reflux (AGER) is relatively prolonged in children with cystic fibrosis (CF). Disparity in CC values within our CF cohort sparked curiosity as to what CC looks like in infants and children with AGER in the physiologic range. The aim of the study was to assess CC in infants and children with normal AGER. Methods: Impedance-pH tracings from our database for infants (⩽12 months) and children (>12 months–18 years) were manually scanned for 2-phase AGER episodes. Tracings were excluded for patients who had AGER Indices >3% (children) or >6% (infants), had positive GER-symptom associations, were on antireflux medications, had a fundoplication, or had impedance studies shorter than 18 hour. In addition to medians (25%–75% interquartile range), we calculated the 95th percentile for the CC duration and the fifth percentile for the CC rate. Results: Two-phase AGER episodes were detected in 44 infants and 60 children. The median CC duration was 64.3 seconds (51.0–91.6 seconds) for infants and 37.5 seconds (27.7–52.4 seconds) for children. The median CC rate was 0.0622 pH units/second (PU/second) (0.0354–0.0946 PU/second) for infants and 0.0928 PU/second (0.0631–0.2057 PU/second) for children. The CC duration at the 95th percentile was 148.5 seconds for infants and 114.4 seconds for children. The CC rate at the fifth percentile was 0.0088 PU/second for infants and 0.0465 PU/second for children. Conclusions: We report reference values for CC in infants and children who have normal acid reflux. These values should not be used as “cutoff values” because they were derived from infant and children cohorts that did not include individuals with intermediate AGER.

Effect of Severity of Esophageal Acidification on Sleep vs Wake Periods in Infants Presenting with Brief Resolved Unexplained Events

OBJECTIVES To describe the pattern of gastroesophageal reflux (GER) events in wake and sleep states with increasing acid reflux index (ARI) in neonates and to test the hypothesis that GER-related symptoms are frequent in ARI >7% in wake state. STUDY DESIGN Infants underwent 24-hour pH-impedance studies with 6-hour concurrent video-polysomnography studies. Data were stratified based on the 24-hour ARI (% duration that esophageal pH is <4) into ARI < 3% (normal), ARI 3 ≥ to ≤7% (intermediate), and ARI >7% (abnormal). GER frequency, clearance mechanisms, and symptoms were distinguished during wake state and sleep state. RESULTS Total wake and sleep duration was similar (P ≥ .2) in all ARI groups. Acidic events were frequent with increasing ARI in wake state vs sleep state (P ≤ .03). The symptom index increased with increasing ARI (P ≤ .02) in both wake state and sleep state. Acid clearance time increased with increasing ARI in wake state (P ≤ .02). In ARI > 7% vs ARI ≤ 7%, frequency of acidic GER events was higher (P ≤ .02) in wake state and sleep state; proximal migration of acid (P = .03) and acid clearance time were higher in wake state (P = .0005) only. Symptom index was higher in ARI >7% vs ARI ≤ 7% in wake state (P < .0001), comparable in normal vs intermediate (P = .4), and higher in abnormal vs intermediate (P = .0004) groups. CONCLUSIONS Severe esophageal acid exposure (ARI >7%) is associated with increased reflux-associated symptoms in wake state. Sleep state appears to be protective regardless of ARI, likely because of greater chemosensory thresholds. Attention to posture and movements during wake state can be helpful. Scrutiny for non-GER etiologies should occur for infants presenting with life-threatening symptoms.

Gastroesophageal Reflux Affects Sleep Quality in Snoring Obese Children.

Purpose This study was performed to evaluate the quality of sleep in snoring obese children without obstructive sleep apnea (OSA); and to study the possible relationship between sleep interruption and gastroesophageal reflux (GER) in snoring obese children. Methods Study subjects included 13 snoring obese children who were referred to our sleep lab for possible sleep-disordered breathing. Patients underwent multichannel intraluminal impedance and esophageal pH monitoring with simultaneous polysomnography. Exclusion criteria included history of fundoplication, cystic fibrosis, and infants under the age of 2 years. Significant association between arousals and awakenings with previous reflux were defined by symptom-association probability using 2-minute intervals. Results Sleep efficiency ranged from 67-97% (median 81%). A total of 111 reflux episodes (90% acidic) were detected during sleep, but there were more episodes per hour during awake periods after sleep onset than during sleep (median 2.3 vs. 0.6, p=0.04). There were 279 total awakenings during the sleep study; 56 (20.1%) of them in 9 patients (69.2%) were preceded by reflux episodes (55 acid, 1 non-acid). In 5 patients (38.5%), awakenings were significantly associated with reflux. Conclusion The data suggest that acid GER causes sleep interruptions in obese children who have symptoms of snoring or restless sleep and without evidence of OSA.

Metabolomic responses to lumacaftor/ivacaftor in cystic fibrosis

Cystic fibrosis (CF) is a life‐limiting disease caused by a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Lumacaftor/Ivacaftor is a novel CFTR modulator approved for patients that are homozygous for Phe508del CFTR, but its clinical effectiveness varies amongst patients, making it difficult to determine clinical responders. Therefore, identifying biochemical biomarkers associated with drug response are clinically important for follow‐up studies.