Published online January 2, 2007
PEDIATRICS
Vol. 119
No. 1
January 2007, pp.
118-122
(doi:10.1542/peds.2006-1753)
Will Esophageal Impedance Replace pH Monitoring?
Yvan Vandenplas, MD, PhDa,
Silvia Salvatore, MDb,
Mario C. Vieira, MDc and
Bruno Hauser, MDa
a Department of Pediatrics, Academisch Ziekenhuis Vrije Universiteit Brussel, Brussels, Belgium
b Clinica Pediatrica di Varese, Università dell'Insubria, Varese, Italy
c Hospital Pequeno Príncipe, Curitiba, Brazil
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ABSTRACT
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Esophageal impedance, a technique based on the fact that the passage of a bolus changes the impedance between esophageal segments, is being used more and more. Multiple esophageal impedance combined with pH monitoring is advocated to become the preferred technique to measure acid and nonacid gastroesophageal reflux. Compared with pH monitoring, impedance has the advantage of being independent of pH and, as a consequence, is better adapted to measure reflux (especially in the postprandial period when reflux is buffered) and detect symptoms associated with nonacid- or weakly acid-reflux episodes. Conversely, the analysis of an impedance tracing requires more time and knowledge than a pH tracing and is possibly subjected to higher interobserver variability. Day-to-day reproducibility and interobserver variability are considerable. Episodes detected only by pH monitoring or impedance are numerous in pediatrics; therefore, pH monitoring and impedance should be associated in analyses of multiple esophageal impedance combined with pH monitoring. Up to now, there has been a striking absence of literature showing attempts to link data from diagnostic procedures to clinical outcome in symptomatic patients. Furthermore, data suggesting that impedance does offer a clear-cut benefit in pediatric clinical routine are missing. High cost of the material and the investment in time necessary for interpretation of the recording remain a handicap. However, because pH monitoring is part of impedance technology, it is likely that the latter will soon replace pH monitoring despite the current need of scientific evidence demonstrating a relation between symptoms, esophageal damage or response to reflux treatment, and results of multiple esophageal impedance combined with pH monitoring.
Key Words: impedance • pH monitoring • gastroesophageal reflux • child
Abbreviations: GER—gastroesophageal reflux • MII-pH—multiple esophageal impedance combined with pH monitoring
In the 1980s, the development of esophageal pH monitoring changed the workup on gastroesophageal reflux (GER) substantially. Because of the many publications and because it was possible for the first time to measure the number and duration of acid-reflux episodes over a period of 24 hours, the technique was (too?) widely applied. It has taken years to know the advantages but also the disadvantages of 24-hour esophageal pH monitoring. Mainly because of the shortcoming of all the procedures to diagnose GER disease, impedance often is presented as the ultimate solution. In this review we aim to inform the nonspecialist about the actual knowledge but, even more, the missing information about impedance, providing a critical view on this new but promising technique. We also aim to inform the nonspecialist about today's knowledge and shortcomings of intraluminal impedance combined with pH recording.
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PRINCIPLES OF THE TECHNIQUE
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The basic principle of impedance is identical to pH monitoring: registration of esophageal data through a probe placed transnasally and connected to a recorder. After a registration of 24 hours, the recording is downloaded into specific software that provides a trace and, if selected, an automatic analysis. The impedance probe has a diameter similar to the pH probe, has several (mostly 6) rings to measure impedance, and also includes 1 (or 2) pH sensors. As a consequence, multiple esophageal impedance combined with pH monitoring (MII-pH) records simultaneously in at least 6 esophageal sites. Impedance (ie, electrical resistance) is determined by the quantity and flux of ions into the tissue. There is always a certain impedance between esophageal walls (called the impedance baseline). When the esophagus is empty, the impedance is high, whereas the passage of a volume bolus decreases impedance and the passage of air increases the impedance. Therefore, MII-pH may detect all episodes of reflux, identifying the content, direction, and localization of the reflux independent from its pH level. Just as for pH monitoring, criteria to define an episode of reflux needed to be established. It is well known that for pH monitoring, a drop in esophageal pH below 4.0 has been arbitrarily considered as the cutoff value for acid reflux. Equally for impedance, a drop in impedance by >50% from baseline has been arbitrarily defined as typical for the passage of a volume bolus. Furthermore, an impedance episode is considered if it reaches at least 3 consecutive rings (each ring is separated by a minimum of 1 cm in the probes for infants). If the drop in impedance starts at the upper level, it is a swallow; if the drop starts at the lower level, it is a reflux episode.
The diagnostic sensitivity of multiple intraluminal impedance may correspond to that of the pH probe in untreated patients but is superior to the pH probe in patients treated with antacid medication.1 Episodes detected only by pH monitoring are numerous in pediatrics; therefore, pH monitoring should be included in MII-pH analyses.1 The reproducibility of MII-pH recording on 2 consecutive days is rather poor, especially for nonacid reflux.2 The limits of agreements for the number of acid- and nonacid-reflux episodes at day 3 were 0.2 to 5.3 and 0.04 to 8.6 times the value obtained at day 1, respectively.2 Reproducibility of pH monitoring on 2 consecutive days was previously reported to have Pearson correlation coefficients ranging from 0.88 to 0.98.3 Two independent investigators confirmed >95% of the reflux events detected by the automatic MII-pH analysis but added 
33% of acid-, weakly acid-, and nonacid-reflux episodes.4 However, the agreement between both investigators for newly detected reflux episodes in 24-hour MII-pH was only 50%.3 Interobserver variability was reportedly much better in impedance recordings in neonates during a period of 6 hours.5
Frequently, when a new technique is developed to replace an older one, the newer one is, in general, considerably more expensive. Both the device and the electrodes for impedance are currently considerably more expensive than those used for pH metry.
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TECHNICAL ADVANTAGES AND DISADVANTAGES
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Impedance allows the detection of the frequency, the height (in the esophagus), and duration of reflux episodes independent of the pH of the refluxate. Experience with pH monitoring has shown the pitfalls of an arbitrary pH cutoff limit such as 4.0. Indeed, it is very likely that a pH of 3.9, 4.0, or 4.1 has exactly the same clinical relevance. A similar comment can be made for impedance; the automatic analysis considers only a drop of impedance of 
50% as a reflux episode. However, it is very likely that a drop of 49% can be attributed to a reflux episode also. Although impedance allows or better necessitates a manual analysis, the relevant question that remains is: What is the decrease in impedance needed to be considered as a reflux episode? Moreover, the drop in impedance is not related to the volume of the refluxate. If pH monitoring would be performed with a probe with multiple pH sensors, it would also be possible to determine the height of the refluxate. Thus, the major difference between both techniques is the detection of nonacid reflux. As a consequence, another fundamental questions arises: What is the clinical relevance of nonacid, weakly acid, and alkaline reflux?
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NONACID REFLUX
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Up to now there has been consensus that investigations measuring reflux during the postprandial period (ultrasound, radiology, scintigraphy) are of limited value in the diagnosis of GER disease because of the high prevalence of GER in the postprandial period. The pH of reflux during a postprandial period is mostly >4 (thus commonly regarded as nonacid on the basis of pH-monitoring criteria). In a study of 16 preterm infants, when a nasogastric tube passed the cardia, impedance showed an increase in postprandial reflux from 72 to 122 episodes.6 In 7 healthy preterm newborns who received nasogastric milk feeding, the mean prevalence of nonacid reflux (29 episodes per 24 hours) was >2 times the prevalence of acid reflux (12 episodes per 24 hours), and 80% of these reflux episodes reached the proximal esophagus.7
Conversely, Condino et al8 reported that the distribution of acid and nonacid reflux was almost equal in a group of 34 infants aged between 2 and 11 months: 47% of the reflux episodes were acid, and 53% were nonacid. The impact of postprandial nonacid reflux decreases with age, because the number of feedings decreases and, with it, the total duration of postprandial periods and the overall buffering effect of milk.8 Although the symptom correlation (within a 5-minute window) is similar between acid and nonacid reflux (25.2% vs 24.6%), reflux reaching the proximal esophagus seems more frequently associated with pain and burping.8
The impact of position was analyzed through combined manometry and impedance in 10 healthy preterm infants (35–37 weeks' postmenstrual age): 89 reflux episodes were recorded (74% were liquid, 14% were air, and 12% were of mixed content). In the right-lateral position, the number of reflux episodes (as well as the total number of liquid episodes) was significantly higher than in the left-lateral position despite a faster gastric emptying in the right-lateral position, which suggests that the major pathophysiological mechanism causing the reflux episodes was inappropriate transient relaxations of the lower esophageal sphincter.9 Similar findings were reported recently by another group: the number of acid- and nonacid-reflux episodes was significantly smaller when the subjects were in the prone and left-side sleeping position in comparison to those in the supine and right-side positions.10
In addition to position, the effects of formula feeding and alginate on height, frequency, and type of reflux have also been studied. Wenzl et al11 evaluated the effect of antiregurgitation formula with MII-pH in 14 infants. The efficacy of an antiregurgitation formula on the frequency and severity of reflux was confirmed in this trial, with a more pronounced effect for nonacid reflux. Although there was a trend for reflux to be less proximal, the difference was not significant. Impedance showed that alginates such as Gaviscon do not decrease the number of postprandial episodes of GER but may marginally decrease the height of the refluxate.12
It is unlikely that nonacid reflux is of major importance in patients who present with esophagitis (but endoscopy and esophageal biopsy are the gold standard for diagnosing mucosal damage). Bilirubin is known to be at least equally toxic to the esophageal mucosa as acid, but the number of patients with esophagitis and only pathologic alkaline or nonacid reflux and normal acid reflux is restricted.13,14 No data exist correlating MII-pH results and esophageal biopsies.
Many children present with chronic respiratory symptoms related to GER: chronic bronchitis, wheezing, chronic cough, and infant apnea. A strong relation between acid and nonacid GER and respiratory abnormalities was reported in 1 study. Impedance recorded 364 episodes of reflux, of which only 11.4% were acid, in a group of 22 children who presented with repetitive regurgitation and chronic respiratory symptoms.15 Of these reflux episodes, 312 (85%; 12% of which were acid) could be associated with irregular breathing. In a minority of these episodes (19), oxygen desaturations of >10% occurred (19% [3 of 19] of these episodes were acid). Analysis of the polysomnographic recording revealed 165 episodes of apnea, of which 30% were associated with a reflux episode. Again, the majority (78%) of reflux episodes were detected with impedance only.15 However, the association between pathologic central, obstructive, or mixed apnea has not been demonstrated (but has also not been well studied yet), and clear cutoff values discriminating normal from pathologic children still need to be determined. When compared with pH monitoring, impedance could better demonstrate that apnea of short duration is a physiologic phenomenon occurring frequently in relation to an episode of GER.16 In a group of 22 infants, 364 episodes of GER were detected with impedance. Apneas (165) were documented by visual validation records. Of these events, 49 (30%) were associated with GER17 and 11 (22.4%) showed acid reflux (pH < 4). Nineteen preterm infants (gestational age: 30 weeks) who presented with apnea were studied at a mean age of 26 days (range: 13–93 days); 2039 episodes of apnea (median: 67; range: 10–346), 188 oxygen desaturations (median: 6; range: 0–25), 44 bradycardias (median: 0; range: 0–24), and 524 episodes of GER (median: 25; range: 8–62) were detected.18 The frequency of apnea in a 20-second period before and after an episode of GER was not different from the frequency of apnea not related to a reflux episode (0.19/minute [range: 0.00–0.85/minute] vs 0.25/minute [range: 0.00–1.15/minute]).18 The analysis and conclusions were identical for oxygen desaturations and bradycardias.18 Mousa et al19 analyzed the temporal relationship between apnea and GER in a group of 25 infants who presented with an apparent life-threatening event or pathologic apnea. A time interval of as long as 5 minutes between apnea and reflux was considered acceptable to demonstrate a "temporal link" between the 2 phenomena. In total, 527 episodes of apnea were recorded, but only 80 (15.2%) were temporally linked to a reflux episode (despite the large criterion of 5 minutes). Of these 80 episodes, 37 (7.0% of the total number of apnea episodes) were related to an acid-reflux episode and 43 (8.2%) were related to a nonacid-reflux episode. Thus, even considering a time interval of as long as 5 minutes, one can conclude that the relation between reflux and apnea exists but is rare.19
Chronic respiratory manifestations such as coughing and wheezing are accepted to occur in children with reflux disease. Rosen and Nurko20 reported their experience in 28 children (mean age: 6.5 ± 5.6 years) with chronic respiratory disease who were under treatment with antacid medications. A total of 1822 episodes of reflux were measured with MII-pH; 45% of them were nonacid. Multivariate analysis showed a stronger association between respiratory symptoms with nonacid-reflux episodes than with acid-reflux episodes. Also, the height of the refluxate in the esophagus was associated with respiratory symptoms: the higher the reflux, the stronger the association.20 The association score between symptoms and episodes of reflux detected with impedance and pH monitoring was 35.7 ± 28.5 and 14.6 ± 18.9 (P = .002), respectively. However, it seems obvious that pH monitoring detects less reflux during antacid treatment and that such a pH-monitoring score also has to be considered as abnormal. In a selected group of 22 adults, a relation between chronic coughing and GER has been accurately studied by combined manometry and MII-pH.21 Using a time frame of 2 minutes and symptom-association probability, 69.4% of the coughing episodes were considered "independent" of a reflux episode. When a "reflux-cough" sequence occurred, the reflux in 65% of the cases was acid, weakly acid in 29%, and weakly alkaline in 6%.21
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CONCLUSIONS
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Impedance is a costly and time-consuming technique that allows detection of all reflux events. pH-only episodes are numerous in pediatrics and should be included in MII-pH analyses.1 Day-to-day variability of the number of nonacid-reflux episodes is considerable,2 and the interpretation of nonacid-reflux episodes has a high interobserver variability.4 Although impedance clearly registers more GER episodes than pH monitoring, the advantage and/or relevance of recording "more" episodes of GER in daily clinical practice still needs confirmation. Today, impedance still has to be considered as a (clinical) research tool. Clinical relevance of detection of weakly acid and nonacid reflux is also still a matter of research, because published data are currently inconclusive and specific treatment is not available. Symptom-correlation analysis, especially for extraesophageal symptoms, is likely to be more convincing with impedance than with pH monitoring,22 but this evidence is still missing. Nevertheless, because pH monitoring is part of impedance recording, it is very likely that impedance will be performed more frequently in routine practice.
From the data reviewed above, it is currently difficult to draw conclusions on the clinical advantage of MII-pH because of the heterogenicity of the studies (in terms of population recruited and technical criteria such as time and symptoms association), the lack of normal data, and the lack of outcome measures. More homogeneous criteria of inclusion and analysis associated with a complete baseline and prospective clinical features are clearly needed in future reports. Impedance is a new, promising technical development that offers unexplored possibilities for investigating GER. Although many authors suggest a degree of usefulness, the technique is still in a phase in which the added value to other techniques in the routine workup of patients needs to be evaluated and demonstrated.
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FOOTNOTES
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Accepted Sep 14, 2006.
Address correspondence to Yvan Vandenplas, MD, PhD, Department of Pediatrics, Academisch Ziekenhuis Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. E-mail: yvan.vandenplas{at}az.vub.ac.be
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
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ABSTRACT
PRINCIPLES OF THE TECHNIQUE
