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Keywords:

  • gastro-oesophageal reflux;
  • multichannel intraluminal impedance;
  • pH monitoring;
  • preterm infants

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Abstract  Gastro-oesophageal reflux (GOR) is common in preterm infants. Combined multichannel intraluminal impedance and pH monitoring (pH-MII) is emerging as an useful tool to study both acid and non-acid GOR in this population. We aimed to highlight main advantages and limits of pH-MII in preterm infants and to test whether the inclusion of GOR episodes detected only by pH monitoring details better the features of GOR. Fifty-two symptomatic preterm infants underwent a 24-hour, continuous and simultaneous measurement of pH-MII. Each layout was analyzed using two different options: option 1 included GOR episodes detected by MII and then classified as acid or non-acid according to the associated pH change; option 2 included GOR episodes detected by MII and also GOR episodes detected only by pH sensor. By adopting option 1, a total number of 2834 GOR episodes was detected by MII: 2162 of them were characterized as non-acid and 672 were characterized as acid. The median (range) number of acid MII-GOR episodes was 10 (1–52); the median (range) number of non-acid MII-GOR episodes was 36.5 (2–119). Median (range) acid MII-GOR-bolus exposure index was 0.28% (0.02–2.73%); median (range) non-acid MII-GOR-bolus exposure index was 1.03% (0.06–38.15%). By adopting option 2, an average of 53.2 acid GOR episodes and an average of 11% oesophageal exposure to acid GOR more than by option 1 was detected. An accurate and detailed description of GOR in preterm infants can be obtained only by including in the analysis all acid GOR episodes detected by pH sensor.


Abbreviations
aMII-GOR-BEI

acid-MII-GOR-bolus exposure index

AOP

apnoea of prematurity

EP

early postprandial

GOR

gastro-oesophageal reflux

GORD

gastro-oesophageal reflux disease

LOS

lower oesophageal sphincter

LP

late postprandial

MII

multichannel intraluminal impedance

NaMII-GOR-BEI

non-acid-MII-GOR-bolus exposure index

TLOSRs

transient lower oesophageal sphincter relaxations

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Gastro-oesophageal reflux (GOR) is common in preterm infants due to some physiological factors, such as the immaturity of lower oesophageal sphincter (LOS), the supine lying position and the gastric filling with a high volume of fluid.1 In some patients, GOR can become clinically relevant because it can trigger respiratory phenomena, such as apnoea of prematurity2 and delay hospital discharge.3

Twenty-four-hour pH monitoring which has represented the standard technique for the diagnosis of GOR in infants,4 recognizes GOR as a drop in oesophageal pH to less than 4. Thus, it detects acid GOR, whereas it cannot identify non-acid GOR episodes; this is relevant in newborns because milk buffers gastric pH for a long time after meal.5 Therefore, pH monitoring has crucial limitations when applied to preterm infants because it may underestimate the frequency of reflux episodes and may not identify cardio-respiratory events resulting from non-acid reflux.6

Impedance monitoring is a new technique that can be used to detect the flow of fluids and gas through hollow viscera. By a multichannel intraluminal impedance (MII) device, GOR can be detected, regardless of its acidity, by differences in electrical impedance between the mucosal surface, fluids and gas that surround the catheter.7 MII is highly sensitive to very small fluid bolus movements,8 permits to distinguish retrograde bolus movement (GOR) from antegrade movement (swallow), recognizes physical composition of refluxate and records the distance from LOS reached by each GOR episode.

In adults patients,9 combined MII and pH monitoring (pH-MII) is emerging as an useful tool to study both acid and non-acid reflux, providing detailed characterization of the reflux episode, including determination of the composition (gaseous, liquid or mixed) and the height reached by the refluxate. GOR is primarily detected by MII as a drop in impedance to at least 50% of the baseline value, and it is then characterized as acid or non-acid according to the associated pH change; any pH measurement non-associated with a corresponding MII measurement is excluded from the analysis.

Studies performed in infants and newborns are few and heterogeneous because some of them have included and some others have excluded GOR episodes detected only by pH monitoring.10,11 In the present study, we aimed to highlight the main advantages and limits of combined pH-MII in preterm infants and to test whether the inclusion of GOR episodes detected only by pH monitoring can better detail the features of GOR in this population.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Fifty-two (31 male) preterm infants with mean gestational age 29 weeks (range, 24–33) and a mean birth weight of 1274 g (range, 500–2250) were enrolled in the study at a mean age of 38 days (range, 7–127) and a mean weight of 1733 g (range, 1170–2880), as they had frequent regurgitations and postprandial desaturations. In addition, 36/52 patients had postprandial apnoeas, 8/52 showed failure to thrive, 12/52 had bradycardia and 11/52 had both postprandial apnoeas and bradycardia. All of them were otherwise healthy at the moment of examination. None had malformation or major gastro-intestinal problems, nor was taking drugs influencing gastro-intestinal motility or gastric acidity.

All the infants tolerated at least 100 mL kg−1day−1 of extracted human milk, fortified with 3% FM85 (Nestlé, Vevey, Switzerland) and/or of a standard preterm formula. During the 24-hour pH-MII monitoring, the infants were fed eight or seven meals, with a 3 or 3 ½ h interval between consecutive meals, respectively.

Each patient underwent a 24-hour, continuous and simultaneous measurement of intra-esophageal pH and multichannel intraluminal electrical impedance (Sandhill Scientific Inc, Highland Ranch, CO, USA). Written informed consent was obtained from the parents of each infant before the examination.

The single use, flexible pH-MII probe (Comfortec® pH-MII Sandhill Scientific) contained seven impedance rings which constituted six dipolar impedance channels, and one antimony electrode for pH detection, located in the middle of the distal impedance dipole. The distance between each of the impedance rings was 1.5 cm, except for the distance between the two distal ones which was 2 cm.

The pH sensor, located in the middle of the distal couple of impedance electrodes, was calibrated before each analysis using two different pH buffer solutions (one of pH 4.0 and the other of pH 7.0). The catheter was inserted through a nostril without sedation and was placed under fluoroscopy. The tip was fixed about 1 cm above the LOS. Before removal, the position of the catheter was compared with the initial position by checking the depth mark on the catheter in order to exclude a displacement. Data were acquired on a portable Sleuth Sandhill Scientific system, and then stored in a personal computer; they were analyzed by a specific software (BioVIEW Analysis Sandhill Scientific, version 5.0.9) and confirmed by direct visual evaluation of the layout. Both the two provided options for layout analysis [exclusion (Option 1) or inclusion (Option 2) of GOR episodes detected only by pH monitoring)] were performed, and data obtained by MII and pH monitoring were collected separately.

MII data

Impedance monitoring detected a GOR episode (MII-GOR) if there was a sequential drop in impedance to less than 50% of baseline value, starting distally and propagating retrogradely to at least the next two more proximal measuring segments (about 4.5 cm above LOS). A GOR episode was then defined as acid or non-acid according to the associated pH change: all the episodes detected by MII with a concomitant decrease in pH to less than 4 were defined as acid MII-GOR episodes, while all the episodes detected by MII with a pH ≥ 4 were defined as non-acid MII-GOR episodes.12 The duration of each GOR episode was recorded as the time (in s) between the onset of GOR in the most distal impedance channel and the recovery of the impedance baseline value in the same channel. The total percent time with MII-GOR episodes in the oesophagus was indicated as bolus exposure index (BEI), and further separated into acid MII-GOR-bolus exposure index (aMII-GOR-BEI) and non-acid MII-GOR-bolus exposure index (NaMII-GOR-BEI). Physical composition of the refluxate was also identified, and MII-detected episodes were divided into liquid, gaseous and mixed. Gaseous reflux was defined as a rapid increase in impedance that occurred simultaneously or retrogradely in at least two oesophageal measuring segments.13 Migration height of GOR episodes was recorded as the maximum distance from LOS reached by the refluxate inside the oesophagus: only liquid and mixed GOR episodes had migration height quantification.

Finally, each layout was visually evaluated in order to recognize drops in impedance to less than 50% of baseline value limited to the distal dipole, in the absence of any impedance change in the other dipoles and with a concomitant pH >4. These impedance drops which were considered as non-acid GOR episodes limited to distal oesophagus (short non-acid GOR) were undetectable by MII automatic scan. In fact, MII automatic scan was ‘blind’ to all GOR episodes which did not reach at least three consecutive impedance rings (approximately 4 cm above LOS).

pH monitoring data

An acid GOR episode was recorded by pH monitoring as a pH drop to less than 4.14 To be detected by the pH sensor, this pH drop had to last at least 5 s. The total percent time of oesophageal exposure to a pH <4 was named Reflux Index (RIpH). This latter measurement included periods of acid oesophageal exposure associated with retrograde bolus movement (detected by MII) and periods with acid oesophageal exposure non-associated with retrograde bolus movement. The presence of a single measuring sensor, located approximately at 2 cm above LOS, did not allow the detection of the height reached by GOR episodes.

As suggested by the manufacturer, each GOR episode, detected by MII and by pH monitoring, was further checked by a direct visual evaluation of the layout for additional confirmation. Data obtained by MII and by pH monitoring were then combined in order to test whether the inclusion in the analysis of GOR episodes detected only by pH monitoring (Option 2) can better detail the features of GOR in our study population.

Statistical analysis

The Bland and Altman method with Bland–Altman plots (Med Calc 9.3.9.0, Med Calc Software, Mariakerke, Belgium) was used to test the agreement between the two options of analysis, one including and the other excluding GOR episodes detected only by pH monitoring (Option 1 and Option 2, respectively).

Wilcoxon test (Statistical Package for the Social Sciences for Windows version 16.0; SPSS Inc., Chicago, IL, USA) was performed to highlight differences between early and late postprandial period, while Sperman Rank Correlation Test (SPSS 16.0 for Windows) was performed in order to evaluate whether there existed a relationship between the number of acid GOR episodes detected by MII and by pH monitoring. A P value ≤0.05 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Fifty-two preterm infants were enrolled in this study. The test was well tolerated by all them and their clinical status remained stable throughout the 24-hour examination. Probe position did not change during any of the examinations. A total number of 2834 GOR episodes was detected by MII (Table 1): 2162 of them were characterized as non-acid and 672 were characterized as acid. During each 24-hour analysis, a median of 44 (range, 0–118) liquid episodes, 3 (range, 0–69) gaseous episodes and 4.5 (range 0–46) mixed episodes were detected. The median (range) number of acid MII-GOR episodes was 10 (1–52); the median (range) number of non-acid MII-GOR episodes was 36.5 (2–119). Median (range) aMII-GOR-BEI was 0.28% (0.02–2.73%); median (range) NaMII-GOR-BEI was 1.03% (0.06–38.15%).

Table 1.   Twenty-four-hour combined multichannel intraluminal impedance and pH monitoring in 52 preterm infants: GOR indexes detected by MII (excluding GOR episodes detected only by pH monitoring) and by pH monitoring
 MIIpH Monitoring
  1. GOR, gastroesophageal reflux; MII, multichannel intraluminal impedance.

  2. Values are expressed as median (range).

GOR episodes (n)52.5 (6–137)44 (2–197)
Acid GOR episodes (n)10 (1–52)44 (2–197)
Non-acid GOR episodes (n)36.5 (2–119)Undetectable
Esophageal acid exposure (%)0.28 (0.02–2.73)8.35 (0.09–45.78)
Esophageal non-acid exposure (%)1.03 (0.06–38.15)Undetectable
Mean height (cm)5.48 (3.06–7.41)Undetectable

Three thousand four hundred forty-three acid GOR episodes were detected by pH monitoring: six hundred seventy-two of them were detected also by MII (as described above), while 2771 were detected only by the pH sensor. The median number (range) of GOR indexes detected by pH monitoring during each 24-hour analysis compared with those detected by MII are reported in Table 1. All GOR episodes detected by the automatic scan of the software were confirmed by the direct visual evaluation of the layout.

A positive correlation was found between the number of acid GOR episodes detected by MII and GOR episodes detected by pH monitoring (ρ = 0.690, P = 0.000). Seven hundred thirty-seven (median: 12, range: 3–57) short non-acid GOR episodes were detected by a visual evaluation of the layout.

Fig. 1 shows the difference between the two methodological options in the detection of acid GOR episodes: the mean difference between the two options (Option 1 –Option 2) was −53.2. In other words, the inclusion in the analysis of GOR episodes detected only by pH monitoring allowed the detection of an average of 53.2 acid GOR episodes more.

image

Figure 1.  Bland–Altman plot showing the lack of agreement between two options of automated analysis (Option1 and Option2) in the detection of acid gastro-oesophageal reflux (GOR) episodes. The difference between the options (Option1 − Option2) against their mean is plotted.

Download figure to PowerPoint

Fig. 2 shows the difference between the two options in the detection of oesophageal exposure to acid GOR: the mean difference between the two options (Option1 − Option2) was −0.11. In other words, the inclusion in the analysis of GOR episodes detected only by pH monitoring allowed the detection of an average of 11% oesophageal exposure to acid GOR more.

image

Figure 2.  Bland–Altman plot showing the lack of agreement between two options of automated analysis (Option1 and Option2) in the detection of oesophageal exposure to acid gastro-oesophageal reflux (GOR). The difference between the options (Option1 − Option2) against their mean is plotted.

Download figure to PowerPoint

As the features of GOR changed during postprandial hours,11 each postprandial period was divided into two semi-periods [named early postprandial (EP) and late postprandial (LP) periods] of equal duration, in order to further test the diagnostic performance of the so-called Option 2. GOR indexes measured in the EP period were compared with those measured in the LP period (Table 2). Total number of GOR episodes and all the acid GOR indexes were significantly higher during LP than during EP. On the other side, non-acid GOR indexes and mean height of GOR episodes were significantly higher during EP than during LP.

Table 2.   Twenty-four-hour combined multichannel intraluminal impedance and pH monitoring in 52 preterm infants: comparison of the main GOR indexes between early and late postprandial period, including in the analysis GOR episodes detected only by pH sensor
 EPLPP
  1. EP, early postprandial period; LP, late postprandial period; GOR, gastroesophageal reflux; RIpH, total percent time of oesophageal exposure to a pH <4; MII, multichannel intraluminal impedance; aMII-GOR-BEI, acid bolus exposure index; NaMII-GOR-BEI, non-acid bolus exposure index.

  2. Values are expressed as median (range). A P value <0.05 was considered statistically significant.

GOR episodes (n) 40.5 (9–112)61 (6–171)0.000
pH-only GORs (n)4 (0–41)41.5 (2–156)0.000
Acid MII-GOR (n)1 (0–21)9 (1–34)0.000
Non-acid MII-GOR (n)27.5 (2–111)6 (0–33)0.000
Short non-acid MII-GOR (n)6 (0–26)6 (1–28)0.509
Mean height (cm)4.05 (2.75–6.68)3.22 (1.35–5.50)0.000
RIpH (%)0.61 (0–34.17)11.83 (0.15–46.62)0.000
aMII-GOR-BEI (%)0.03 (0–2.24)0.41 (0.03–2.91)0.000
NaMII-GOR-BEI (%)1.47 (0.05–6.81)0.17 (0–1.68)0.000

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References

Combined pH-MII monitoring is emerging as a very useful tool to diagnose GOR in infants. The software can use two different options of analysis, including or excluding GOR episodes detected only by pH monitoring. In the few studies conducted in preterm newborns, both the options of analysis allowed by the automatic scan have been used10,11 but a comparison between them has never been carried out. Our study shows that the best choice of analysis in preterm infants is to take into account GOR episodes detected by MII and also GOR episodes detected only by the pH sensor. In fact, this option allowed the detection of a significantly higher number of acid GOR episodes than MII alone.

This finding is probably specific for preterm infants, and may be related to the different height that a GOR episode has to reach to be detected by the pH sensor and by the MII detection system. The pH sensor was located in the distal oesophagus at a distance of about 1.5 cm above LOS, and thus it was able to detect short acid GOR episodes limited to this portion of the oesophagus. On the contrary, the detection of a GOR episode by MII was based on the measurement of the impedance drop in at least two consecutive dipoles, corresponding to three impedance rings; therefore, the minimal height a GOR episode has to reach to be detected by MII was about 4–4.5 cm above LOS. All GOR episodes limited to the distal half of the oesophagus cannot be detected by MII in preterm infants and thus GOR episodes detected only by the pH sensor have to be included in the analysis. A similar relationship between the position of the pH probe in the oesophagus and the number of GOR episodes detected was described in adults;15 in that study, the authors measured oesophageal pH at two different levels inside the oesophagus and showed that acid exposure was greater at the distal level than at proximal one.

It has been suggested in experimental models, and recently confirmed also in human studies, a link between GOR and apnoea of prematurity (AOP);2 it has been also demonstrated that GOR episodes limited to distal oesophagus, which were found in our study to be a great proportion of total GOR, can evoke an apnoea by a reflex mechanisms.16 For this reason, it is mandatory to optimize the detection of both distal and proximal episodes of acid and non-acid GOR, in order to better describe the association between GOR and chronic and recurrent respiratory problems of preterm infants.

A previous study17 showed that in infants with gastro-oesophageal reflux disease (GORD), the number of transient lower oesophageal sphincter relaxations (TLOSRs) was similar to normal infants: however, infants with GORD had a higher proportion of TLOSRs associated with acid reflux. Thus, an underestimation of acid GOR episodes could lead to a global underestimation of GOR. However, the pH sensor is able to detect only acid distal GORs, whereas it misses non-acid distal GORs. Therefore only an improvement of the MII probe by reducing the distance between the impedance dipoles might allow the detection of almost all GOR episodes in preterm infants. A short segmental non-acid GOR is probably an innocuous events; however, this methodological limitation should be taken into account if a study of comparison between pathological events (e.g. AOP and GOR) is performed.

In the present study we have also shown that an accurate evaluation of both acid and non-acid GOR is particularly useful in analyzing GOR features during postprandial period. Non-acid GORs were prevalent during the first postprandial hours, whereas acid GORs were prevalent during the second postprandial hours.

The height reached by GOR episodes soon after meal was significantly higher than in later period, and this is probably related to the filling status of the stomach. Immediately after meal, the stomach is almost full of milk and thus, when a GOR episode occurs, it is likely to be non-acid and to have a proximal extent. On the contrary, during LP period, gastric content recovers acidity while its volume decreases; thus, the majority of GOR episodes are acid GOR and detected only by pH probe, because they are limited to distal oesophagus.

In conclusion, this study clarifies some methodological aspects of combined pH-MII monitoring in preterm infants, suggesting that an accurate and detailed description of GOR may be obtained only by including in the analysis all acid GOR episodes detected by pH electrode. Further improvement of the instrument would be advisable for a even more complete evaluation of GOR in preterm infants.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. References
  • 1
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    Singh P, Taylor RH, Colin-Jones DG. Simultaneous two level oesophageal pH monitoring in healthy controls and patients with oesophagitis: comparison between two positions. Gut 1994; 35: 3048.
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    Perkett EA, Vaughan RL. Evidence for a laryngeal reflex in some human preterm infants. Acta Paediatr Scand 1982; 71: 96972.
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    Omari TI, Barnett CP, Benninga MA et al. Mechanisms of gastro-oesophageal reflux in preterm and term infants with reflux disease. Gut 2002; 51: 4759.