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ARTICLE |
a Department of Pediatric Surgery
c Neonatal Medicine Unit, Children's Hospital Virgen del Rocío, Seville, Spain
b Department of Medical Physiology and Biophysics, University of Seville, Seville, Spain
d Femu, University of Technology, Aachen, Germany
e Centre of Gastroenterological Research, Catholic University of Leuven, Leuven, Belgium
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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METHODS. Esophageal impedance was recorded for 24 hours in 21 asymptomatic preterm neonates by replacing the conventional feeding tube with a specially designed feeding tube that included 9 impedance electrodes (8 French). All neonates were asymptomatic, with spontaneous breathing. Reflux monitoring was performed after comprehensive explanation and on receipt of written parental consent. Esophageal and gastric pH were monitored using a separate parallel pediatric catheter (6 French). According to the corresponding pH change, impedance-detected reflux was classified as acid, weakly acidic, and weakly alkaline. For each infant, the total number of reflux events, the acid exposure and bolus exposure times at 2 cm above the respiratory inversion point, and average proximal extent of reflux were calculated.
RESULTS. Twenty-six preterm neonates were recruited into this study. A preliminary analysis was performed, and tracings were classified according to their quality and the presence of technical artifacts (spontaneous pH and impedance drifts, esophageal probe migration, and dysfunction of 1 or more impedance channels). Five studies were excluded because of 1 or more technical artifacts; a total of 21 neonates represent the final cohort included. At birth, the infants had a median postmenstrual age of 32 weeks, and the measurements were performed at a median age of 12 days. The total recording time was 23.7 ± 2 hours. Gastric pH was higher than 4 during 69.3 ± 20.4% of the recording time. The median number of reflux events in 24 hours was 71, 25.4% (range: 0%–53.1%) of which were acid, 72.9% (range: 45.3%–98.0%) were weakly acidic, and 0% (range: 0%–8.1%) were weakly alkaline. Compared with fasting periods, feeding periods tended to be associated with a higher number of total reflux events per hour. The acidity of reflux, however, was significantly different: during fasting, the number of acid reflux episodes per hour was higher, whereas during feeding, the number of weakly acidic reflux episodes was increased. Most reflux events were only liquid, whereas gas was present either mixed with liquid or pure only in 7.7% of all reflux episodes detected. The proximal esophageal segments were reached in 90% of reflux episodes. Reflux-related acid exposure (pH drops associated with impedance-detected reflux) was 1.66% (range: 0%–6.43%), whereas total acid exposure (associated and not associated with reflux detected by impedance) was 5.59% (range: 0.04%–20.69%). There was no relationship between the number or acidity of reflux events and anthropometric parameters such as weight and gestational age.
CONCLUSIONS. We present the first study using 24-hour impedance-pH recordings in asymptomatic premature neonates. Previous studies that used pH-metry suggested that neonatal cardiorespiratory symptoms could be related to acid gastroesophageal reflux. However, pH-metry could not detect accurately weakly acidic or nonacid reflux. Our healthy premature neonates had 
70 reflux events in 24 hours, 25% of which were acid, 73% were weakly acidic, and 2% were weakly alkaline. The number of reflux events per hour (2–3 per hour) was slightly lower than that described in premature neonates with cardiorespiratory events (4 per hour). We confirmed that weakly acidic reflux is more prevalent than acid reflux, particularly so during the feeding periods. In contrast, similar to healthy adults, weakly alkaline reflux was very rare. We confirmed findings from previous studies in which most reflux events were pure liquid during both fasting and during postprandial periods and gas reflux was very rare. As in neonates with cardiorespiratory symptoms, the majority of reflux events in asymptomatic preterms reached the proximal esophagus or pharynx, and there were no differences between acid and weakly acidic reflux. The lack of differences between asymptomatic and diseased infants contravenes the hypothesis for macro- or microaspiration but does not exclude hypersensitivity to reflux as a cause for respiratory symptoms. The acid exposure that was related to reflux events and detected by impedance was significantly lower than the total acid exposure during 24 hours. Increased acid exposure could be attributable to pH-only reflux events or, less frequently, to slow drifts of pH from baselines at 5 to values <4. These changes were not accompanied by a typical impedance pattern of reflux but by slow drifts in impedance in 1 or 2 channels. Our findings confirm the need for the use of impedance together with pH-metry for diagnosis of all gastroesophageal reflux events. The relationship between gastroesophageal reflux and cardiorespiratory events in neonates and older infants has been studied extensively. The current evidence for such a relationship is controversial. This study provides values of impedance-pH monitoring for acid, weakly acidic, and weakly alkaline reflux from healthy preterm neonates that can be used for comparison when evaluating gastroesophageal reflux in preterm infants with a cardiorespiratory disease.
Key Words: gastroesophageal reflux disease • preterm infants • impedance • pH monitoring
Abbreviations: GER—gastroesophageal reflux • GERD—gastroesophageal reflux disease • TLESR—transient lower esophageal sphincter relaxation • IQR—interquartile range
Gastroesophageal reflux (GER) is a physiologic process and is considered pathologic (GER disease [GERD]) only when it causes symptoms or results in pathologic complications. It is common in preterm infants and occurs in healthy neonates.1,2 Excessive irritability and crying, vomiting/regurgitation, and feeding intolerance are the most common symptoms, whereas esophagitis is extremely rare in children who are younger than 4 months.3
It has been suggested that when untreated, increased GER might impede growth as a result of energy deprivation or cause cardiorespiratory symptoms.2,4 Transient lower esophageal sphincter relaxation (TLESR) is the predominant mechanism of GER in both healthy premature infants and those with GERD.2,5
Twenty-four-hour pH monitoring is used in adults and children for diagnosis of pathologic GER. Abnormal reflux is considered with detection of increased esophageal acid exposure; however, in neonates, relatively few GER episodes cause esophageal acidification to pH <4.6 Although premature infants may have a well-developed capacity to acidify gastric pH to <4, they receive frequent feeds, often every 2 to 4 hours, which can induce a weaker acid secretory response than that observed in older infants and adults.7–9 As a consequence, gastric pH may be >4 for prolonged periods, and reflux of gastric contents might be less acidic or even alkaline. Esophageal impedance monitoring is currently considered the most sensitive technique to detect GER of liquid and/or gas, regardless of its acidity.
Once reflux is detected by impedance, it is characterized by simultaneous pH-metry as acid, weakly acidic, or weakly alkaline.10 The role of weakly acidic and alkaline reflux in the pathophysiology of GERD in preterm infants is not clear. To date, studies that have used impedance-pH in neonates assessed the association between nonacid reflux and cardiorespiratory symptoms,11 but no impedance data from healthy preterm neonates have been available to determine whether those symptomatic neonates had an increased number of weakly acidic reflux or increased reactivity to a physiologic number of reflux events. Comparison with reflux patterns in healthy preterm neonates will allow for a better understanding of pathologic conditions. Therefore, the aim of this study was to investigate the rate and characteristics of GER (acid and weakly acidic), detected by impedance-pH, in healthy preterm neonates.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Esophageal impedance-pH was monitored using a specially designed 5-French feeding tube that incorporated 9 impedance electrodes 15 mm apart (total external diameter 8 French; Femu, Aachen, Germany). The feeding-impedance tube was placed in such a way that 4 impedance segments (15 mm long) spanned the esophageal body, 2 proximal segments monitored the oropharyngeal area, and 2 distal segments recorded from the lower esophageal sphincter and proximal stomach (Fig 1).
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Esophageal and gastric pH were monitored using a separate parallel pediatric catheter 6 French (Medical Measurement Systems, Enschede, Netherlands) with 2 antimony electrodes separated by 50 mm and an external reference electrode. Esophageal pH was measured at 2 cm proximal to the respiratory inversion point, previously determined manometrically using a pull-through technique. The pH electrodes were calibrated with buffer solutions of 1 and 7 before and after the measurements, and pH signals were digitized and stored together with the impedance recording. The position of the middle electrode between impedance segments 5 and 4 corresponded to the position of the esophageal pH sensor and was corrected, if necessary, after routine thorax radiograph controls (Fig 1).
Esophageal impedance-pH monitoring was performed with the infant in supine position and was started during the breaks between 2 feedings. The beginning and the end of each feeding and bathing period were noted by the attending nurse in the impedance monitoring system.
Data Analysis
The 24-hour pH-impedance recording was uploaded onto a personal computer and displayed on a single screen for computer-assisted manual analysis, using a specialized software program (Review, A. Andrioli, MSci, PhD, 1996). Feeding and fasting periods were analyzed separately, and prolonged crying and bathing instances were excluded from analysis.
The impedance and pH recordings was analyzed independently for GER. GER was detected by impedance and defined as a sequential, orally progressing drop in impedance to <50% of the baseline values starting distally in the esophageal body and propagating retrogradely to at least the next 2 more proximal measuring segments. According to the corresponding pH change, impedance-detected reflux was classified as acid when pH fell below 4 for at least 4 seconds or when pH was already <4, as a decrease of at least 1 pH unit sustained for >4 seconds (Fig 2). Weakly acidic reflux was defined as a pH drop of at least 1 pH unit sustained for >4 seconds with the basal pH remaining between 7 and 4 (Fig 3). Reflux was considered weakly alkaline when there was impedance evidence of reflux but the pH did not drop below 710 (Fig 4).
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that occurred simultaneously or retrogradely in at least 2 esophageal measuring segments. For each reflux episode as determined by impedance-pH, the associated gas-liquid pattern was classified as (1) mixed reflux of liquid and gas or (2) liquid reflux. The proximal extent of each reflux event was evaluated from the impedance tracings. For each infant, the total number of reflux events (acid, weakly acidic, and weakly alkaline), the acid exposure and bolus exposure times at 2 cm above the respiratory inversion point, and average proximal extent of reflux were calculated. Esophageal acid exposure was calculated in 2 ways: (1) reflux-related acid exposure was calculated as the time with pH <4 associated with impedance-detected reflux, divided by total monitoring time; and (2) total esophageal acid exposure was calculated as the total time (reflux related and not reflux related) with pH <4 divided by total monitoring time. The bolus exposure time was measured from the most distal impedance segment in the esophageal body. Bolus exposure time is the sum of all periods with impedance detection of volume reflux. Each of these periods was limited from liquid bolus entry (impedance drop to <50% of baseline) to liquid bolus clearance (impedance return to >50% of baseline). Acid clearance and volume clearance were defined as acid exposure and bolus exposure times, respectively, divided by the total number of reflux episodes.
Statistical Analysis
When values were not distributed normally, they were presented as median, interquartile range (IQR), and 95th percentile. Median values were compared using the Wilcoxon signed rank test. Linear regression analysis was used to correlate anthropometric values with reflux characteristics. P < .05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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At birth, the infants had a median postmenstrual age of 32 weeks (IQR: 30–34), cranial perimeter of 29 cm (IQR: 27–30.8), length of 42 cm (IQR: 39–44), actual median weight of 1740 g (IQR: 1500–1910), and birth weight of 1585 g (IQR: 1368–1860), and the measurements were performed at a median age of 12 days (IQR: 9–17.5).
Gastric pH Data
Gastric pH was monitored continuously at 2 to 3 cm distal to the respiratory inversion point, during both fasting and feeding periods. Gastric pH was >4 during 69.3 ± 20.4% of the recording time.
Impedance-pH Data
The mean ± SD total recording time was 23.7 ± 2 hours. Tracings were analyzed separately during fasting periods (15 ± 2.1 hours) and feeding periods (8.7 ± 1.8 hours). The impedance basal value in the distal esophagus was 1750 (IQR: 1500–2050). GER induced impedance drops to 400 to 500 . The median number of reflux events in 24 hours was 71 (IQR: 51–76.5; 95th percentile: 100.7), 25.4% (range: 0%–53.1%) of which were acid, 72.9% (range: 45.3%–98.0%) were weakly acidic, and 0% (range 0%–8.1%) were weakly alkaline (Table 1). The median number of reflux events during fasting in 24 hours was 37 (IQR: 31–45; 95th percentile: 71), 42.2% (range: 0%–61.8%) of which were acid, 57.8% (range: 35.3%–97.1%) were weakly acidic, and 0% (range: 0%–10.7%) were weakly alkaline. During feeding periods, the median number of reflux events was 28 (IQR: 19–36; 95th percentile: 48), 5.0% (range: 0%–43.5%) of which were acid, 94.4% (range: 56.5%–100%) were weakly acidic, and 0% (range: 0%–2.8%) were weakly alkaline.
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Esophageal volume clearance time (measured by impedance) was significantly faster than esophageal chemical clearance (measured by pH). The median bolus clearance time (volume clearance of individual reflux events) was 9.2 seconds compared with a median of 20.8 seconds for acid clearance.
The esophageal mucosa was exposed to reflux volume (detected by impedance) during a median of 0.73% (range: 0.3%–1.22%) of the total recording time (fed: 0.89% [range: 0.20%–1.47%]; fasting: 0.56% [range: 0.18%–1.41%]). Reflux-related acid exposure (pH drops associated with impedance-detected reflux) was 1.66% (range: 0%–6.43%; fed: 0.10% [range: 0%–10.33%]; fasting: 1.36% [range: 0%–8.3%]), whereas total acid exposure (associated and not associated with reflux detected by impedance) was 5.59% (range: 0.04%–20.69%; fed: 2.35% [range: 0%–12.60%]; fasting: 7.23% [range: 0%–24.55%]).
pH-only reflux events (ie, abrupt pH drops from >4 to <4 without an impedance change) were observed on 134 occasions (median: 6 per patient), whereas slow drifts of pH across pH 4 were observed on a total of 41 occasions in 12 patients (1–9 per patient). There was no relationship between the number or the acidity of reflux events and anthropometric parameters such as weight (P = .15) and gestational age (P = .29).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Previous studies using pH-metry have suggested that neonatal cardiorespiratory symptoms could be related to acid GER.12 However, pH-metry could not detect accurately weakly or nonacidic reflux, and no data from healthy preterm neonates were available for comparison.
The main results of this study were that healthy premature neonates had 70 reflux events in 24 hours, 25% of which were acid, 73% were weakly acidic, and 2% were weakly alkaline. Compared with fasting periods, feeding periods tended to be associated with a higher number of reflux events per hour, which were mostly weakly acidic. The number of reflux events per hour (2–3 per hour) was slightly lower than that described in premature neonates with cardiorespiratory events (4 per hour).13 Most reflux events were pure liquid, during both fasting and postprandial periods. Gas reflux was rare. The refluxate reached the proximal esophagus in 90% of events, and the volume clearance, as a result of peristalsis, was significantly faster than the esophageal chemical clearance (measured by pH). The esophageal mucosa was exposed to refluxed volume during <1% of the total recording time. Esophageal acid exposure was significantly higher during fasting than during feeding periods. The acid exposure that was related to individual reflux events, however, was significantly lower than the total acid exposure as a result of a combination of mechanisms such as straining and slow pH drifts. There was no relationship between patterns or number of reflux events and anthropometric parameters such as weight and gestational age.
Combined esophageal impedance and pH monitoring allow detection of GER of gas and acid or nonacid liquids, and this now is considered to be the best technique to detect and characterize GER.10 Ambulatory and stationary impedance-pH devices now are commercially available, and increasing use of this technique is expected. Normal values and reproducibility tests of ambulatory 24-hour impedance-pH monitoring obtained in healthy adults have been documented.14,15
Previous studies used impedance to evaluate reflux in asymptomatic preterm infants. One short study (4 hours) combined both impedance and manometry,1 and another 24-hour study used impedance without pH.16
The recordings that were taken in this study were performed on neonates without any cardiorespiratory symptoms, staying in the neonatal critical care unit only for feeding and monitoring. They required nasogastric feeding because of immaturity to oral feeding.17 The measurements were made possible by replacing the conventional feeding tube with a specially designed feeding tube that included the impedance electrodes. This was performed after comprehensive explanation and on receipt of full parental consent.
To use the set of values presented in this study for comparison, it should be considered that our patients were studied in supine position and had a nasogastric catheter. Recent studies demonstrated that preterm infants in supine position have less reflux than in right lateral decubitus,1 whereas the presence of a nasogastric catheter that straddles the lower esophageal sphincter might significantly increase the number of reflux episodes.16
The quality of the 24-hour impedance pH recordings was good enough for clear recognition of the typical reflux pattern by impedance from other changes that were provoked by movements or crying. The recordings were analyzed manually to assess technical artifacts. The visual recognition of reflux and artifact patterns in the current study potentially would help the completion of the development of an automatic computer analysis, currently under way.18,19
We confirmed that weakly acidic reflux is more prevalent than acid reflux, particularly so during the feeding periods. In contrast, similar to healthy adults, weakly alkaline reflux was very rare.14,15 Although the gastric pH could be highly modified by the constant presence of milk, the refluxates rarely had a pH of 7 or more. Furthermore, the esophageal basal pH was lower in our population (5–6) compared with that observed in adults.
Compared with fasting periods, feeding periods tended to be associated with a higher number of reflux events per hour and were mostly weakly acidic. Although this did not reach statistical significance, there was a clear trend toward an increased number of reflux episodes during the feeding periods. It is very possible that this is attributable to gastric distension and triggering of TLESRs.1,2,20
We confirmed findings from previous studies in which most reflux events were pure liquid during both fasting and postprandial periods and gas reflux was very rare.1 However, we acknowledge that our definition for gas reflux was obtained from experience in adults, and it might be necessary to redefine gas reflux in neonates, as detected by impedance, considering the presence of a nasogastric feeding tube and continuous supine position.
As in neonates with cardiorespiratory symptoms, the majority of reflux events in asymptomatic preterms reached the proximal esophagus or pharynx, and there were no differences between acid and weakly acidic reflux.21 The lack of differences between asymptomatic and diseased infants contravenes the hypothesis for macro- or microaspiration but does not exclude hypersensitivity to reflux as a cause for respiratory symptoms.
In healthy preterm infants, the volume clearance after reflux was very fast and efficient, the mucosa exposure to volume being <1% of the total recording time. These data confirm the maturity for eliciting complete primary and secondary peristalsis.5
As expected by the higher prevalence of weakly acidic reflux during feeding, esophageal acid exposure was more significant during fasting periods. The acid exposure that was related to reflux events that were detected by impedance was significantly lower than the total acid exposure during 24 hours. This finding confirms recent observations in infants22 and adults.15,23 Despite such differences, the majority of our asymptomatic infants had a median total esophageal acid exposure within accepted normal values for this population.6
The reason for the difference between reflux-related and total acid exposure is not completely clear. Increased acid exposure could be attributable to pH-only reflux events or, less frequently, slow drifts of pH from baselines at 5 to values <4. These changes were not accompanied by a typical impedance pattern of reflux but by slow drifts in impedance in 1 or 2 channels. Formal analysis of nontypical impedance changes during pH-only and drift events currently are under way to establish the definite sensitivity and specificity of impedance for diagnosis of minute volume acid reflux. Our findings confirm the need for the use of impedance together with pH-metry for diagnosis of all GER events.10
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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FOOTNOTES |
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Address correspondence to Daniel Sifrim, MD, PhD, Faculty of Medicine K.U. Leuven, Lab G-I Physiopathology, Gasthuisberg University Hospital, Herestraat 49, 3000, Leuven, Belgium. E-mail: daniel.sifrim{at}med.kuleuven.ac.be
Financial Disclosure: Prof Silny is the inventor of the application of intraluminal impedance to study gastroesophageal reflux. Prof Sifrim receives a research grant from Sandhill Scientific (manufacturer of impedance equipment).
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This article has been cited by other articles:
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  S. Michail Gastroesophageal Reflux Pediatr. Rev., March 1, 2007; 28(3): 101 - 110. [Full Text] [PDF]
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