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Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis
JCF-01288; No of Pages 8
Journal of Cystic Fibrosis xx (2015) xxx – xxx www.elsevier.com/locate/jcf
Original Article
Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis☆ Bruno Hauser a,⁎, Jean De Schepper a , Anne Malfroot a , Elke De Wachter a , Iris De Schutter a , Kathelijn Keymolen b , Yvan Vandenplas a a b
Department of Paediatrics, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium Centre for Medical Genetics, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium Received 30 July 2015; revised 15 December 2015; accepted 15 December 2015 Available online xxxx
Abstract Background: Gastro-oesophageal reflux (GOR) is common in patients with cystic fibrosis (CF). The aim of this study was to investigate the relationship between gastric emptying (GE) and GOR in children with CF. Methods: Multichannel intraluminal impedance-pH monitoring (MII-pH) to measure GOR and GE breath test (GEBT) to measure GE were performed in 28 children with symptoms suggestive for GOR disease (GORD) (group 1). GEBT was performed in another 28 children with/ without GOR symptoms who agreed to undergo GEBT but not MII-pH (group 2). Results: In group 1, we found increased acid GOR (AGOR) in 46.4% and delayed GE (DGE) in 21.4% but no relationship between increased AGOR and DGE. There was no DGE in group 2. We found DGE in 10.7% and rapid GE in 12.5% of the whole group. Conclusions: Almost half of the children with CF and symptoms suggestive for GORD have increased AGOR and almost a quarter has DGE. However, there was no relation between GOR and GE. © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Gastric emptying; Gastro-oesophageal reflux; Cystic fibrosis; Children; Multichannel intraluminal impedance-pH monitoring; breath test
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C-gastric emptying
Abbreviations: GOR, Gastro-oesophageal reflux; CF, Cystic fibrosis; GE, Gastric emptying; MII-pH, Multichannel intraluminal impedance-pH monitoring; GEBT, Gastric emptying breath test; AGOR, Acid gastro-oesophageal reflux; DGE, Delayed gastric emptying; GI, Gastrointestinal; GORD, Gastro-oesophageal reflux disease; NAGOR, Nnon-acid gastro-oesophageal reflux; NGE, Normal gastric emptying; RGE, Rapid gastric emptying; 99mTS, 99mTechnetium scintigraphy; 13 C-OBT, 13C-octanoic acid breath test; 13C-ABT, 13C-acetate breath test; PI, Pancreatic insufficiency; PS, Pancreatic sufficiency; BMI, Body mass index; FEV1, Forced expired volume at 1 s; PPI, Proton pump inhibitors; LOS, Lower oesophageal sphincter; MII, Multichannel intraluminal impedance; MII-GOR, Multichannel intraluminal impedance gastro-oesophageal reflux; MII-AGOR, Multichannel intraluminal impedance acid gastro-oesophageal reflux; MII-NAGOR, Multichannel intraluminal impedance non-acid gastro-oesophageal reflux; RI, Refluxindex; IRIS, Infra Red Isotope; t1/2-GE, Gastric half emptying time; P90, Percentile 90; P10, Percentile 10. ☆ Part of this work was presented as poster presentation and published as abstract in the Journal of Cystic Fibrosis at the: 32nd European Cystic Fibrosis Conference, Brest, France, 2009 and 36th European Cystic Fibrosis Conference, Lissabon, Portugal, 2013. ⁎ Corresponding author at: Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, BE-1090 Brussels, Belgium. Tel.: + 32 24775780; fax: + 32 24775783. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.jcf.2015.12.015 1569-1993/© 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Please cite this article as: Hauser B, et al, Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/ 10.1016/j.jcf.2015.12.015
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B. Hauser et al. / Journal of Cystic Fibrosis xx (2015) xxx–xxx
1. Introduction Cystic fibrosis (CF) is an inherited disease affecting not only the lungs but also the entire digestive system. Gastrointestinal (GI) symptoms are the most important non-pulmonary manifestations of this disease. Gastro-oesophageal reflux (GOR) and GOR disease (GORD) are more frequent in adults and children with CF compared with healthy controls. Most GOR studies in patients with CF have been performed with pH-metry which measures only acid GOR (AGOR). Multichannel intraluminal impedance-pH monitoring (MII-pH) measures AGOR and non-acid GOR (NAGOR) which can be both increased in CF. Delayed gastric emptying (DGE) can contribute to GOR. DGE, normal GE (NGE) as well as rapid GE (RGE) have been reported in adults and children with CF [1–3]. The “gold standard” to measure gastric emptying (GE) is 99m Technetium scintigraphy (99mTS) which is associated with a radiation exposure [4]. For this reason, alternative nonradioactive methods using the stable isotope 13C have been developed. The 13C-octanoic acid breath test (13C-OBT) to measure GE of solids and the 13C-acetate breath test (13C-ABT) to measure GE of liquids were developed [5,6]. We have recently validated the 13C-ABT and the 13C-OBT against 99mTS in children with upper GI symptoms and established normal values for the GE of liquids and solids in healthy children measured with the 13C-ABT and the 13C-OBT (submitted).
To the best of our knowledge, there is only one study in adults (n = 20) and one study in children (n = 15) with CF where MII-pH and GE assessment were both performed in the same patients. Both studies showed an abnormal MII-pH and DGE in 67% and 33% of the adults, and in 54.8% and 33.3% of the children, respectively, but found no correlation between DGE and increased GOR except for a subgroup of adults with DGE and increased acidic duodenogastro-oesophageal reflux [7,8]. The aim of this study was to investigate in children with CF (1) GOR measured with MII-pH, (2) GE measured with GE breath test (GEBT) and (3) the relationship between GOR and GE. 2. Material and methods 2.1. Subjects This prospective study was performed in 56 children with CF. MII-pH was performed in 28 children selected on the basis of GI symptoms (belching, epigastric pain, heartburn, regurgitation, vomiting) and/or respiratory symptoms (signs of unexplained respiratory evolution despite maximal therapy) suggestive for GORD. A GEBT was also performed in these patients (group 1). GEBT alone was performed in another 28 children with CF with/without GOR symptoms selected on the basis that they agreed to undergo a GEBT but not MII-pH (group 2) (Table 1). The diagnosis of CF had been made on the
Table 1 Group 1 (multichannel intraluminal impedance-pH monitoring and gastric emptying breath test) and group 2 (gastric emptying breath test alone): patient characteristics.
Age (years) Gender (boys/girls) (n) Pancreas function (PI/PS) (n) Genotype F508del homozygous (n) F508del heterozygous (n) Others (n) Unknown (n) Weight (kg) Weight SDS (Z-score) Height (cm) Height SDS (Z-score) BMI (kg/m²) BMI SDS (Z-score) FEV1% predicted Colonisation with Pseudomonas aeruginosa (n) Staphylococcus aureus (n) Upper GI symptoms (n) Meconium ileus (n) Intake PPI (n) Intake prokinetics (n) Intake azithromycin (n) Intake insulin (n) Intake laxatifs (n) Intake ursodeoxycholic acid (n)
Group 1 (MII-pH + GEBT) (n = 28)
Group 2 (GEBT alone) (n = 28)
p group 1 versus group 2
4.4 (1–17) 14–14 21–7
9.0 (4–14) 18–10 17–11
0.001 0.280 0.252 0.884
11 7 5 5 16.0 (6.2–55.0) − 1.02 (− 3.15; 1.26) 107.0 (61.0–159.4) − 0.66 (− 6.94; 2.23) 15.0 (11.5–22.3) − 1.06 (− 3.70; 2.97) 95.0 (39.2–129.6)
9 9 4 6 27.5 (16.0–53.0) − 0.47 (− 2.60; 1.89) 132.5 (105.0–175.0) − 0.12 (− 2.15; 2.99) 15.6 (13.2–21.0) − 0.50 (− 2.11; 2.04) 97.5 (37.8–123.1)
0.001 0.007 0.001 0.029 0.252 0.188 0.487
7 18 14 4 12 8 2 2 14 7
8 23 10 5 5 5 2 1 15 5
0.763 0.131 0.280 0.716 0.042 0.342 1.000 0.553 0.789 0.515
Legend: MII-pH: multichannel intraluminal impedance-pH monitoring; GEBT: gastric emptying breath test; PI: pancreatic insufficiency; PS: pancreatic sufficiency; BMI: body mass index; FEV1: forced expired volume in 1 s; GI: gastrointestinal; PPI: proton pump inhibitors. Please cite this article as: Hauser B, et al, Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/ 10.1016/j.jcf.2015.12.015
B. Hauser et al. / Journal of Cystic Fibrosis xx (2015) xxx–xxx
basis of an abnormal sweat test and genotype determination. All subjects were in stable clinical condition at the moment of the investigations and stopped medication known to affect GI motility and gastric acid secretion at least 2 weeks before MII-pH and GEBT were performed. We analysed if one of the following patient characteristics were related to the results of MII-pH and GEBT: age (years), gender (boy, girl), pancreatic exocrine function (pancreatic insufficiency (PI) and pancreatic sufficiency (PS)), genotype (F508del homozygous, F508del heterozygous, other mutations and unknown mutations), weight (kg) and SDS (Z-score), height (cm) and SDS (Z-score), body mass index (BMI) (kg/cm²) and SDS (Z-score), forced expired volume at 1 s (FEV1% predicted), colonisation with Pseudomonas aeruginosa and Staphylococcus aureus, upper GI symptoms (anorexia, belching, bloating, early satiety, epigastric pain, heartburn, nausea, postprandial fullness, regurgitation, vomiting), history of meconium ileus, intake of proton pump inhibitors (PPI), intake of prokinetics, intake of azitromycine, intake of insulin, intake of laxatifs and intake of ursodeoxycholic acid. The children were recruited at the CF clinic of the Universitair Ziekenhuis Brussel, Brussels, Belgium. The local Ethics Committee approved the protocol. Written informed consent was obtained from the parents, and if possible from the children themselves. 2.2. GOR monitoring with MII-pH GOR was measured using ambulatory 24 h MII-pH with a 2.1 mm diameter catheter that comprises 6 electrode pairs to measure oesophageal intraluminal impedance and 2 antimony pH sensors to measure oesophageal and gastric pH (Sleuth, Sandhill Scientific Inc, Highlands Ranch, CO, USA) according to an ESPGHAN EURO-PIG standard protocol [9]. Multichannel intraluminal impedance (MII) GOR (MII-GOR) was defined as a progressing drop in impedance to b 50% of the baseline values starting distally at the lower oesophageal sphincter (LOS) and progressing to at least the next 2 more proximal measuring segments in the oral direction. The MII-GOR was classified as MII-AGOR (pH b 4) or MII-NAGOR (pH ≥ 4) according to the corresponding pH change. The number of MII-AGOR episodes, number of MII-NAGOR episodes and the total number of MII-GOR episodes were calculated. The total 24 h oesophageal acid exposure or refluxindex (RI), corresponding to the percentage of time that the oesophageal pH was below 4, was calculated with the pH-recording independently from the MII-recording. MII-pH results were considered abnormal if values of RI were N 5% corresponding to increased pH-AGOR [10]. 2.3. Test meals for GEBT GEBT tests were performed the day after the MII-pH. According to the age and preference of the children, a standardised liquid or solid test meal was administered in the morning after an overnight fast. The MII-pH catheter was removed in the morning before the GEBT was started. Concerning the GE of liquids, the children ingested within 5 to 10 min a standardised liquid test meal consisting of 200 ml
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milk with a strawberry taste and a caloric content of 112 kcal (INZA Drink®). The milk-drink was labelled with 13C-acetate related to body weight (weight b 10 kg: 20 mg, weight 10– 30 kg: 50 mg, weight N 30 kg: 100 mg) (Eurisotop, SaintAubain, France). Concerning the GE of solids, the children ingested within 10 to 15 min a standardised solid test meal consisting of 1 pancake (17 g wheat flour, 7 g sugar, 1 egg white, 1 egg yolk labelled with 50 μL 13C-octanoic acid (Eurisotop SA, Saint Aubain, France), 40 ml semi-skimmed milk). This pancake batter was baked with 5 g margarine. For consumption, 5 g of sugar was added as sweetener and 100 ml of water was given as drink. The total caloric content was 230 kcal. During the GEBT no drinking or eating and only limited physical activities were allowed. 2.4. GEBT with
13
C-ABT and
13
C-OBT
Breath samples were collected before, every 5 min for the first 40 min and every 10 min for the following 140 min after ingestion of the liquid test meal. Breath samples were collected before and every 15 min for the following 240 min after ingestion of the solid test meal. Breath samples were collected in Infra Red Isotope (IRIS) breath sample aluminium bags with a content of 100 ml connected with a mouthpiece with internal rebreath stop valve. Breath samples were analysed for 13 CO2-enrichment using non dispersive infrared spectrometry with the IRIS-lab-infrared- 13C-isotope-analyser. Non-linear regression analysis of the curve that best fits the cumulative 13 CO2 excretion curve and the 13CO2 excretion by time curve was performed according to the methods described by Ghoos et al. [5] using the IRIS-software “GE2.DEM” for Microsoft Windows (Wagner Analysen Technik, Bremen, Germany). It allowed the calculation of the gastric half emptying time (t1/2-GE) which is the time on which half of the dose of 13 CO2 is excreted of the cumulative 13 CO2 when time is infinite. We defined DGE as t1/2-GE N percentile 90 (P90) and RGE as t1/2-GE b percentile 10 (P10) according to normal values established in healthy children (submitted). 2.5. Statistical analysis Results are presented as medians and ranges. Comparison between groups was done using the Mann-Whitney U test, t-test and ANOVA test when appropriate. Pearson chi-square test and Fisher's exact test were used to compare categorical variables. P b 0.05 was considered statistically significant. Statistics were calculated using the statistical program SPSS version 21.0 for Windows. 3. Results 3.1. Subjects The patients in group 1 were younger than in group 2 so that their weight and height was also lower but BMI was comparable. There were more patients taking PPI in group 1
Please cite this article as: Hauser B, et al, Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/ 10.1016/j.jcf.2015.12.015
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B. Hauser et al. / Journal of Cystic Fibrosis xx (2015) xxx–xxx
compared to group 2. There were no statistically significant differences between both groups for the other patient characteristics (Table 1).
pH-AGOR in comparison with the group with normal pHAGOR. There were no statistically significant differences between the groups with normal and increased pH-AGOR for the other patient characteristics (Table 2).
3.2. GOR monitoring with MII-pH 3.3. GEBT with Increased pH-AGOR was detected in 13/28 children (46.4%). All MII-pH parameters (number of MII-AGOR episodes, number of MII-NAGOR episodes, total number of MII-GOR episodes and RI) were higher in the group with increased pH-AGOR in comparison with the group with normal pH-AGOR. Of the total number of MII-GOR episodes, 2/3 were MII-AGOR episodes and 1/3 were MII-NAGOR episodes (p = 0.0001). There was no statistically significant difference for t1/2-GE of solids and liquids between the groups with increased and normal pH-AGOR. There were fewer patients with meconium ileus and a strong trend for more girls and more patients with upper GI symptoms in the group with increased
13
C-ABT and
13
C-OBT
DGE was found in 6/28 (21.4%) of the children from group 1 and in 0/28 (0%) of the children from group 2 but there were more children with NGE and RGE in group 2 in comparison with group 1: NGE in 20/28 (71.4%) from group 1 versus 23/28 (82.1%) from group 2 and RGE in 2/28 (7.2%) from group 1 versus 5/28 (17.9%) from group 2 (p = 0.024). DGE, RGE and NGE were present in respectively 6/56 (10.7%), 7/56 (12.5%) and 43/56 (76.8%) of all the children that underwent a GEBT (Table 3). Children with RGE were older so that their height was higher and there was a strong trend for a higher weight but their BMI was comparable in comparison with children with
Table 2 Group 1 (multichannel intraluminal impedance-pH monitoring and gastric emptying breath test): multiple intraluminal impedance-pH monitoring parameters, gastric emptying breath test parameters and patient characteristics of the group with normal multiple intraluminal impedance-pH monitoring and the group with abnormal multiple intraluminal impedance-pH monitoring.
Refluxindex (%) MII-AGOR episodes (n) MII-AGOR episodes (%) MII-NAGOR episodes (n) MII-NAGOR episodes (%) MII-GOR episodes (n) t1/2-GE solids (min) t1/2-GE liquids (min) Age (years) Gender (boys/girls) (n) Pancreas function (PI/PS) (n) Genotype F508del homozygous (n) F508del heterozygous (n) Others (n) Unknown (n) Weight (kg) Weight SDS (Z-score) Height (cm) Height SDS (Z-score) BMI (kg/m²) BMI SDS (Z-score) FEV1% predicted Colonisation with Pseudomonas aeruginosa (n) Staphylococcus aureus (n) Upper GI symptoms (n) Meconium ileus (n) Intake PPI (n) Intake prokinetics (n) Intake azithromycin (n) Intake insulin (n) Intake laxatifs (n) Intake ursodeoxycholic acid (n)
Group normal MII-pH (n = 15)
Group abnormal MII-pH (n = 13)
p group normal MII-pH versus group abnormal MII-pH
2.2 (0.1–4.0) 14 (2–33) 69.0 (28.6–95.0) 6 (1–22) 27.6 (5.0–71.4) 20 (7–52) 138 (88–528) 95 (83–106) 4 (2–9) 10–5 10–5
10.4 (6.9–29.0) 29 (8–83) 63.6 (30.5–98.5) 16 (1–64) 32.0 (1.5–69.5) 51 (22–112) 165 (115–911) 79 (66–134) 6 (1–17) 4–9 11–2
0.0010 0.004 0.593 0.015 0.560 0.001 0.420 0.564 0.216 0.058 0.274 0.091
6 2 2 5 15.9 (9.6–26.8) − 1.06 (− 3.15; 0.27) 105.0 (75.0–131.0) − 0.49 (− 6.94; 1.67) 14.5 (11.5–21.3) − 0.12 (− 3.70; 2.97) 97.4 (39.2–129.6)
5 5 3 0 20.0 (6.2–55.0) − 0.99 (− 1.87; 1.26) 118.5 (61.0–159.4) − 0.73 (− 2.46; 2.23) 15.3 (12.7–22.3) − 0.63 (− 3.29; 0.52) 94.9 (49.6–125.6)
0.104 0.277 0.337 0.541 0.204 0.976 0.593
2 10 5 4 5 3 0 0 7 3
5 8 9 0 7 5 2 2 7 4
0.126 0.778 0.058 0.044 0.274 0.281 0.115 0.115 0.705 0.512
Legend: MII-pH: multichannel intraluminal impedance-pH monitoring; MII-AGOR: multichannel intraluminal impedance acid gastro-oesophageal reflux; MII-NAGOR: multichannel intraluminal impedance non-acid gastro-oesophageal reflux; MII-GOR: multichannel intraluminal impedance gastro-oesophageal reflux; t1/2-GE: gastric half emptying time; PI: pancreatic insufficiency; PS: pancreatic sufficiency; BMI: body mass index; FEV1: forced expired volume in 1 s; GI: gastrointestinal; PPI: proton pump inhibitors. Please cite this article as: Hauser B, et al, Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/ 10.1016/j.jcf.2015.12.015
B. Hauser et al. / Journal of Cystic Fibrosis xx (2015) xxx–xxx Table 3 Group 1 (multichannel intraluminal impedance-pH monitoring and gastric emptying breath test), group 2 (gastric emptying breath test alone) and group 1 + 2: gastric emptying results.
DGE NGE RGE
Group 1 (MII-pH + GEBT) (n = 28)
Group 2 (GEBT alone) (n = 28)
Group 1 + 2 (all GEBT) (n = 56)
6 (21.4%) 20 (71.4%) 2 (7.2%)
0 (0%) 23 (82.1%) 5 (17.9%)
6 (10.7%) 43 (76.8%) 7 (12.5%)
Legend: MII-pH: multichannel intraluminal impedance-pH monitoring; GEBT: gastric emptying breath test; DGE: delayed gastric emptying; NGE: normal gastric emptying; RGE: rapid gastric emptying; p of group 1 versus group 2 = 0.024.
DGE. There were no statistically significant differences between the groups with an NGE, DGE and RGE for the other patient characteristics (Table 4).
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3.4. Relation between GE and GOR DGE was present in 3/13 (23.1%) of the children with increased pH-AGOR as well as in 3/15 (20.0%) of the children with normal pH-AGOR (p = 0.393) (Table 5A). There were no statistically significant differences in MII-pH parameters between patients with NGE, DGE and RGE (Table 5B). In accordance, there were no statistically significant correlations between any of the MII-pH parameters and rate of GE (Table 5C). 4. Discussion In the present study we assessed GOR with MII-pH and GE with 13C-ABT or 13C-OBT in children with CF and showed that I) 46.4% have increased pH-AGOR and 21.4% have DGE in a group of patients selected on the basis of GI and/or
Table 4 Group 1 (multichannel intraluminal impedance-pH monitoring and gastric emptying breath test) + group 2 (gastric emptying breath test alone): gastric emptying parameters and patient characteristics of group normal gastric emptying, group delayed gastric emptying and group rapid gastric emptying. Group NGE (n = 43)
Group DGE (n = 6)
Group RGE (n = 7)
p NGE vs DGE NGE vs RGE DGE vs RGE
t1/2-GE solids (min)
148 (102–239)
388 (292–911)
92 (83–110)
0.000 0.078 0.000
t1/2-GE liquids (min) Age (years)
81 (66–106) 7.0 (1–17)
134 5.1 (1–9)
9.0 (4–14)
Gender (boys/girls) (n) Pancreas function (PI/PS) (n) Genotype F508del homozygous (n) F508del heterozygous (n) Others (n) Unknown (n) Weight (kg) Weight SDS (Z-score)
23–20 29–14
3–3 4–2
6–1 5–2
0.127 0.249 0.043 0.260 0.976 0.874
15 11 8 9 21.0 (6.2–55.0) − 0.62 (− 2.60; 1.89)
3 2 0 1 15.0 (9.6–38.0) − 1.41 (− 3.15; 1.26)
2 3 1 1 27.0 (16.0–53.0) − 0.59 (− 1.36; 1.16)
Height (cm) Height SDS (Z-score)
123.0 (61.0–175.0) − 0.49 (− 2.46; 2.99)
99.0 (75.0–147.0) − 0.93 (− 6.94; 2.23)
140.0 (105.0–166.0) − 0.13 (− 1.72; 1.39)
BMI (kg/m²) BMI SDS (Z-score)
15.3 (12.6–22.3) − 0.73 (− 3.29; 2.04)
16.2 (11.5–21.3) − 0.46 (− 3.70; 2.97)
15.4 (13.8–19.2) − 0.95 (− 1.65; 0.06)
FEV1% predicted
95.0 (37.8–129.6)
97.0 (39.2–125.6)
102.0 (77.2–110.5)
Colonisation with Pseudomonas aeruginosa (n) Staphylococcus aureus (n) Upper GI symptoms (n) Meconium ileus (n) Intake PPI (n) Intake prokinetics (n) Intake azithromycin (n) Intake insulin (n) Intake laxatifs (n) Intake ursodeoxycholic acid (n)
13 32 16 7 14 9 4 2 20 10
0 3 3 0 2 2 0 0 4 0
2 6 5 2 1 2 0 1 5 2
0.177/0.174 0.238/0.486 0.057/0.117 0.07/0.085 0.165/0.534 0.017/0.072 0.588/0.500 0.707/0.870 0.881/0.666 0.735 0.804 0.656 0.291 0.327 0.221 0.375 0.613 0.747 0.521 0.477 0.351 0.380
Legend: NGE: normal GE; DGE: delayed GE; RGE: rapid GE; t1/2-GE: gastric half emptying time; PI: pancreatic insufficiency; PS: pancreatic sufficiency; BMI: body mass index; FEV1: forced expired volume in 1 s; GI: gastrointestinal; PPI: proton pump inhibitors. Please cite this article as: Hauser B, et al, Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/ 10.1016/j.jcf.2015.12.015
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Table 5 Relation between gastric emptying and gastro-oesophageal reflux. 5A. Relation between results of MII-pH and GEBT
Abnormal MII-pH (n = 13)
Normal MII-pH (n = 15)
DGE (n = 6) NGE (n = 20) RGE (n = 2)
3 (10.7%) 10 (35.7%) 0 (0%)
3 (10.7%) 10 (35.7%) 2 (7.2%)
Legend 5A: MII-pH: multichannel intraluminal impedance-pH monitoring; GEBT: gastric emptying breath test; DGE: delayed gastric emptying; NGE: normal gastric emptying; RGE: rapid gastric emptying; p of group abnormal MII-pH versus group normal MII-pH = 0.393. 5B. Relation between results of GEBT and GOR episodes
Group NGE (n = 20)
Group DGE (n = 6)
Group RGE (n = 2)
p
Refluxindex (%) MII-AGOR episodes (n) MII-AGOR episodes (%) MII-NAGOR episodes (n) MII-NAGOR episodes (%) MII-GOR episodes (n)
5.5 (0.8–13.9) 23 (8–66) 63.6 (30.5–98.5) 10 (1–64) 32.0 (1.5–69.5) 35 (14–95)
4.8 (0.1–29.0) 13 (2–83) 71.4 (28.6–78.9) 10 (2–29) 28.7 (21.1–71.4) 21 (7–112)
3.2 (2.3–4.0) 12 (9–15) 67.8 (45.5–90.0) 10 (1–18) 34.8 (10.0–59.5) 22 (10–33)
0.861 0.356 0.972 0.797 0.957 0.357
Legend 5B: GEBT: gastric emptying breath test; DGE: delayed gastric emptying; NGE: normal gastric emptying; RGE: rapid gastric emptying; MII-AGOR: multichannel intraluminal impedance acid gastro-oesophageal reflux; MII-NAGOR: multichannel intraluminal impedance non-acid gastro-oesophageal reflux; MII-GOR: multichannel intraluminal impedance gastro-oesophageal reflux. 5C. Correlation between results of GE and GOR episodes
t1/2-GE solids (min) (n = 23)
Refluxindex (%) MII-AGOR episodes (n) MII-NAGOR episodes (n) MII-GOR episodes (n)
r r r r
= = = =
− 0.280; p − 0.365; p − 0.257; p − 0.305; p
= = = =
0.207 0.095 0.249 0.168
t1/2-GE liquids (min) (n = 5) r r r r
= = = =
0.319; p = 0.601 − 0.144; p = 0.856 − 0.443; p = 0.557 − 0.197; p = 0.803
Legend 5C: t1/2-GE: gastric half emptying time; MII-AGOR: multichannel intraluminal impedance acid gastro-oesophageal reflux; MII-NAGOR: multichannel intraluminal impedance non-acid gastro-oesophageal reflux; MII-GOR: multichannel intraluminal impedance gastro-oesophageal reflux.
respiratory symptoms suggestive for GORD who agreed to undergo a MII-pH and GEBT, II) none has DGE in a group of patients with/without GOR symptoms selected on the basis that they agreed to undergo a GEBT but not MII-pH, III) 10.7% have DGE and 12.5% have RGE in the whole group, IV) there is no relationship between increased pH-AGOR and DGE, and V) there are no correlations between any of the GORparameters and GE-rate. Feigelson et al. reported in 1975 for the first time increased GOR in adults and children with CF [11]. Meanwhile, more studies have looked at GOR in adults and children with CF. Most studies have used pH-metry which only measures pHAGOR. Several studies using MII-pH which measures pHAGOR, MII-AGOR, MII-NAGOR and MII-GOR have been performed more recently. All the studies have shown an increased pH-AGOR/MII-GOR that varies between 19.2% and 100% of adults and children with CF (Supplemental Table S1). We found in the present study an increased pH-AGOR in 46.4% of children with CF with symptoms suggestive for GORD. The frequency of increased pH-AGOR/MII-GOR is highly variable across the different studies, probably due to patient selection (different ages, different stages of disease, with/without GOR symptoms) and different normal values that were used (Supplemental Table S1). In the present study, it was impossible to determine whether the number of MII-AGOR, MII-NAGOR and MII-GOR episodes was increased as there are no normal values in children. Wenzl et al. proposed to
define arbitrarily an abnormal MII-pH as N 70 MII-GOR episodes in 24 h in patients ≥ 1 year and N 100 MII-GOR episodes in patients b 1 year [9]. If we would apply these normal values to the present study, only 2 patients would have an abnormal MII-pH. Studies using MII-pH have systematically shown a predominance of MII-AGOR over MII-NAGOR in CF [7,8,12–15], what is confirmed by our data. This might be due to an increased gastric acid secretion [16] and decreased gastric neutralisation due to reduced bicarbonate pancreatic secretion in CF [17]. There were fewer patients with meconium ileus and a strong trend for more girls and more patients with upper gastrointestinal symptoms in the group with increased pH-AGOR. Several studies showed that there was no difference in age, gender, pancreatic function, genotype, nutritional status, lung function, Pseudomonas colonisation, meconium ileus and diabetes between patients with CF with abnormal or normal pH-metry / MII-pH [7,8,13,18,19]. Except for meconium ileus, all findings are confirmed by our data. Increased GOR can cause typical oesophageal (heartburn, regurgitation, vomiting) and extra-oesophageal (cough, hoarseness, wheezing) symptoms but can also occur silently in patients with CF [1,2]. The reported incidence of typical GOR symptoms in patients with CF varies between 20.6% and 39% with one exception reporting 94% (adults only) [20–23]. The number of patients with CF with increased pH-AGOR/ MIIGOR that presents with clinical GOR symptoms varies between
Please cite this article as: Hauser B, et al, Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/ 10.1016/j.jcf.2015.12.015
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0% and 100% depending on the study population selection (Supplemental Table S1). In the present study, 8/13 (61.5%) of the children with CF with increased pH-AGOR reported at least 1 typical GOR symptom in comparison with 3/15 (20%) of the children with CF with normal pH-AGOR (p = 0.025). NGE, DGE and RGE have been described in children and adults with CF (Supplemental Table S2). In the present study, we found DGE in 21.4% of children with CF with symptoms suggestive for GORD who agreed to undergo a MII-pH and GEBT but no DGE in the children with CF with/without GOR symptoms who agreed to undergo a GEBT but not MII-pH. The children in the first group were younger and had historically been taking more often PPI in comparison with the children from the second group. This is probably due to the fact that those children were more often believed to have GORD. For the whole group, we found DGE in 10.7% and RGE in 12.5%. This could be expected as we defined DGE as t1/2-GE N P90 and RGE as t1/2-GE b P10 according to normal values established in healthy children (submitted). DGE for solids, solid/ liquid meal and liquids was reported respectively in 72.7%, 89.7% and 33.3% of children with CF [8,24,25]. DGE for solids and liquids was found respectively between 5.8% and 97.0% and between 0% and 67.0% of adults with CF [7,26– 29]. RGE for liquids or solids was also found in 2.0% of adults with CF [26–27]. Pauwels et al. found DGE in 11/33 (33.3%) adults with CF in a study where MII-pH and 13C-OBT were performed at the same time, as we did [7]. They defined DGE as t1/2-GE N 75 min but this value corresponds to P75 of normal values for t1/2-GE in healthy adult volunteers [5]. If we would define DGE as t1/2-GE N P75 in our study, 18/56 (32.1%) of the children with CF would have a DGE which is comparable with the results from Pauwels et al. [7]. The diversity of results found in the studies that examined GE may be explained by different factors. Patients of different ages and stages of disease were included. Different diagnostic methods (13C-OBT, 13C-ABT, magnet-based motility tracking system, marker dilution technique, scintigraphy, ultrasound, wireless motility capsule), protocols (fasting or test meal, test meal type, duration test) and normal values for GE were used (Supplemental Table S2). In the present study, children with RGE were older in comparison with children with DGE. There were however no significant differences for gender, pancreas function, genotype, lung function, colonisation with P. aeruginosa and S. aureus, constipation, diabetes and liver disease between the groups with an NGE, DGE or RGE (Table 4), confirming data from literature [7,8,25,27,30]. DGE may cause symptoms such as anorexia, belching, bloating, early satiety, epigastric pain, nausea, postprandial fullness and vomiting. There is however a poor correlation between clinical manifestations and abnormal GE, and the most important symptoms (bloating, early satiety, epigastric pain, nausea and vomiting) are variably present in patients with CF [26,27]. In the present study, not only 3/6 (50.0%) of patients with DGE but also 5/7 (71.4%) of patients with RGE reported at least 1 GI symptom of abnormal GE. Bodet-Milin et al. showed that 17/29 (58.0%) of patients with CF with DGE had
7
GI symptoms [27]. Bentur et al. showed that 10/13 (76.9%) of the patients with CF with an abnormal myoelectrical activity of the stomach had GI complaints [25]. Increased GOR in patients with CF is most likely promoted by several factors. Increased number of transient LOS relaxations, reduced LOS pressure, and DGE have been proposed as primary mechanisms associated with GOR in CF. Secondary pathophysiological mechanism like chest physiotherapy and cough have also been suggested to provoke GOR in patients with CF [1–3,23,29]. Blondeau et al. showed however that GOR occurs mostly as a primary phenomenon and is not secondary to cough in patients with CF [12,13]. We showed that DGE was not associated with increased pH-AGOR, that there was no difference in MII-pH parameters between patients with NGE, DGE and RGE, and that there were no correlations between the MII-pH parameters and the rate of GE (Table 5A–C). We could not find any relation between GE rate and acid as well as and non-acid GOR in children with CF and symptoms suggestive for GORD. We can confirm the data of Pauwels et al. showing the absence of correlation between MII-pH parameters and GE rate in adults with CF [7]. Caldaro et al. also found no correlation between GE and GOR events that reach the proximal oesophagus and oesophagitis in children with CF [8]. This study has several limitations. Firstly, there is a possible lack of power as no power calculation was performed. Participation to the study was proposed to the population of +/− 80 children with CF in our centre. Secondly, there are some differences between groups 1 and 2 as group 1 includes children who agreed to undergo a MII-pH and GEBT whilst the children in group 2 refused the MII-pH but accepted the GEBT. Retrospectively, children from group 1 presented more symptoms suggesting GORD than those in group 2. Moreover, the only statistical significant differences between patients of groups 1 and 2 were that patients in group 1 were younger and more were taking PPI (Table 1). We speculate that the symptoms of the patients in group 2 were less severe than in group 1, since more children in group 1 were taking PPI. As a consequence, the increased pH-AGOR and DGE in group 1 cannot be extrapolated to the general CF population. In conclusion, we found that in a group of children with CF with symptoms suggestive for GORD who agreed to undergo a MII-pH and GEBT, 46.4% have increased pH-AGOR and 21.4% have DGE but there was no relationship between pH-AGOR and DGE. On the contrary, we found no DGE in a group of children with CF with/without GOR symptoms who agreed to undergo a GEBT but no MII-pH. We finally found 10.7% DGE and 12.5% RGE in the whole group of children with CF which could be expected as DGE was defined as t1/2GE N P90 and RGE was defined as t1/2-GE b P10. Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.jcf.2015.12.015. Conflict of interest statement Anne Malfroot reports grants from Medi Pharma, nonfinancial support from ABBOTT, non-financial support from
Please cite this article as: Hauser B, et al, Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/ 10.1016/j.jcf.2015.12.015
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GILEAD, non-financial support from Novartis, non-financial support from FOREST, and other forms of support from PTC Therapeutics GmbH-Switserland but without conflicts of interest related to this work. Elke De Wachter reports grants from Novartis, grants from Meda Pharma, non-financial support from Abbott, non-financial support from Gilead, nonfinancial support from Novartis, and non-financial support from Forest but without conflicts of interest related to this work. Yvan Vandenplas is consultant for Biocodex, ASPEN, Kabrita and United Pharmaceuticals but without conflicts of interest related to this work. The other authors have no conflicts of interest to report. Acknowledgements This study was partially funded by the “Willy Gepts Fonds” from the Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium. This scientific academic fund had no role in the study design, in the collection, analysis and interpretation of date, in the writing of the manuscript and in the decision to submit the manuscript for publication. References [1] Mousa HM, Woodley FW. Gastroesophageal reflux in cystic fibrosis: current understandings of mechanisms and management. Curr Gastroenterol Rep 2012;14:226–35. [2] Haller W, Ledder O, Lewindon PJ, Couper R, Gaskin KJ, Oliver M. Cystic fibrosis: an update for clinicians. Part 1: nutrition and gastrointestinal complications. J Gastroenterol Hepatol 2014;29:1344–55. [3] Kelly T, Buxbaum J. Gastrointestinal manifestations of cystic fibrosis. Dig Dis Sci Feb 4 2015 [Epub ahead of print]. [4] Abell TL, Camilleri M, Donohoe K, Hasler WL, Lin HC, Maurer AH, et al. Consensus recommendations for gastric emptying scintigraphy: a joint report of the Society of Nuclear Medicine and the American Neurogastroenterology and Motility Society. Am J Gastroenterol 2008; 103:753–63. [5] Ghoos YF, Maes BD, Geypens BJ, Mys G, Hiele MI, Rutgeers PJ, et al. Measurement of gastric emptying rate of solids by means of carbonlabelled octanoic acid breath test. Gastroenterology 1993;104:1640–7. [6] Braden B, Adams S, Duan LP, Orth KH, Maul FD, Lembke B, et al. The 13C-acetate breath test accurately reflects gastric emptying of liquids in both liquid and semisolid test meals. Gastroenterology 1995;108: 1048–55. [7] Pauwels A, Blondeau K, Mertens V, Farre R, Verbeke K, Dupont LJ, et al. Gastric emptying and different types of reflux in adult patients with cystic fibrosis. Aliment Pharmacol Ther 2011;34:799–807. [8] Caldaro T, Alghisi F, De Angelis P, Garganese MC, Rea F, Pizzoferro M, et al. Cystic fibrosis: a surgical matter ? J Pediatr Surg 2014;49:753–8. [9] Wenzl TG, Benninga MA, Loots CM, Salvatore S, Vandenplas Y, on behalf of the ESPGHAN EURO-PIG Working Group. Indications, methodology, and interpretation of combined esophageal impedance-pH monitoring in children: ESPGHAN EURO-PIG standard protocol. JPGN 2012;55:230–4. [10] Pilic D, Fröhlich T, Nöh F, Pappas A, Schmidt-Choudhury A, Köhler H, et al. Detection of gastroesophageal reflux in children using combined multichannel intraluminal impedance and pH measurement: data from the German Pediatric Impedance Group. J Pediatr 2011;158:650–4.
[11] Feigelson J, Sauvegrain J. Letter: Gastro-esophageal reflux in mucoviscidosis. Nouv Presse Med 1975;4:2729–30. [12] Blondeau K, Dupont LJ, Mertens V, Verleden G, Malfroot A, Vandenplas Y, et al. Gastro-oesophageal reflux and aspiration of gastric contents in adult patients with cystic fibrosis. Gut 2008;57:1049–55. [13] Blondeau K, Pauwels A, Dupont LJ, Mertens V, Proesmans M, Orel R, et al. Characteristics of gastro-esophageal reflux and potential risk of gastric content aspiration in children with cystic fibrosis. JPGN 2010;50: 161–6. [14] Doumit M, Krishnan U, Jaffé A, Belessis Y. Acid and non-acid reflux during physiotherapy in young children with cystic fibrosis. Pediatr Pulmonol 2012;47:119–24. [15] Woodley FW, Machado RS, Hayes Jr D, Di Lorenzo C, Kaul A, Skaggs B, et al. Children with cystic fibrosis have prolonged chemical clearance of acid reflux compared to symptomatic children without cystic fibrosis. Dig Dis Sci 2014;59:623–30. [16] Cox KL, Isenberg JN, Ament ME. Gastric acid hypersecretion in cystic fibrosis. JPGN 1982;1:559–65. [17] Soleimani M. Impaired pancreatic ductal bicarbonate secretion in cystic fibrosis. JOP 2001;2:237–42. [18] Heine RG, Button BM, Olinsky A, Phelan PD, Catto-Smith AG. Gastrooesophageal reflux in infants under 6 months with cystic fibrosis. Arch Dis Child 1998;78:44–8. [19] Brodzicki J, Trawinska-Bartnicka M, Korzon M. Frequency, consequences and pharmacological treatment of gastroesophageal reflux in children with cystic fibrosis. Med Sci Monit 2002;8, CR 529-37. [20] Scott RB, O’Loughlin EV, Gall DG. Gastroesophageal reflux in patients with cystic fibrosis. J Pediatr 1985;106:223–7. [21] Vinocur CD, Marmon L, Schidlow DV, Weintraub WH. Gastroesophageal reflux in the infant with cystic fibrosis. Am J Surg 1985;149:182. [22] Sabati AA, Kempainen RR, Milla CE, Ireland M, Schwarzenberg SJ, Dunitz JM, et al. Characteristics of gastroesophageal reflux in adults with cystic fibrosis. J Cyst Fibros 2010;9:365–70. [23] Ledson MJ, Tran J, Walshaw MJ. Prevalence and mechanisms of gastrooesophageal reflux in adult cystic fibrosis patients. J R Soc Med 1998;91: 7–9. [24] Cucchiara S, Raia V, Minella R, Frezza T, De Vizia B, De Ritis G. Ultrasound measurement of gastric emptying time in patients with cystic fibrosis and effect of ranitidine on delayed gastric emptying. J Pediatr 1996;128:485–8. [25] Bentur L, Hino B, Shamir R, Elias N, Hartman C, Eshach-Adiv O, et al. Impaired gastric myoelectrical activity in patients with cystic fibrosis. J Cyst Fibros 2006;5:187–91. [26] Couturier O, Bodet-Milin C, Querellou S, Carlier T, Turzo A, Bizais Y. Gastric scintigraphy with a liquid-solid radiolabelled meal: performances of solid and liquid parameters. Nucl Med Commun 2004;25:1143–50. [27] Bodet-Milin C, Querellou S, Oudoux A, Haloun A, Horeau-Llanglard D, Carlier T, et al. Delayed gastric emptying scintigraphy in cystic fibrosis patients before and after lung transplantation. J Heart Lung Transplant 2006;25:1077–183. [28] Tonelli AR, Drane WE, Collins DP, Nichols W, Antony VB, Olson EL. Erythromycin improves gastric emptying half-time in adult cystic fibrosis patients with gastroparesis. J Cyst Fibros 2009;8:193–7. [29] Mendez BM, Davis CS, Weber C, Joehl RJ, Fisichella PM. Gastroesophageal reflux disease in lung transplant patients with cystic fibrosis. Am J Surg 2012;204:e21–6. [30] Symonds EL, Omari TI, Webster JM, Davidson GP, Butler RN. Relation between pancreatic lipase activity and gastric emptying in children with cystic fibrosis. J Pediatr 2003;143:772–5.
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Journal of Cystic Fibrosis xx (2015) xxx – xxx www.elsevier.com/locate/jcf
Original Article
Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis☆ Bruno Hauser a,⁎, Jean De Schepper a , Anne Malfroot a , Elke De Wachter a , Iris De Schutter a , Kathelijn Keymolen b , Yvan Vandenplas a a b
Department of Paediatrics, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium Centre for Medical Genetics, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium Received 30 July 2015; revised 15 December 2015; accepted 15 December 2015 Available online xxxx
Abstract Background: Gastro-oesophageal reflux (GOR) is common in patients with cystic fibrosis (CF). The aim of this study was to investigate the relationship between gastric emptying (GE) and GOR in children with CF. Methods: Multichannel intraluminal impedance-pH monitoring (MII-pH) to measure GOR and GE breath test (GEBT) to measure GE were performed in 28 children with symptoms suggestive for GOR disease (GORD) (group 1). GEBT was performed in another 28 children with/ without GOR symptoms who agreed to undergo GEBT but not MII-pH (group 2). Results: In group 1, we found increased acid GOR (AGOR) in 46.4% and delayed GE (DGE) in 21.4% but no relationship between increased AGOR and DGE. There was no DGE in group 2. We found DGE in 10.7% and rapid GE in 12.5% of the whole group. Conclusions: Almost half of the children with CF and symptoms suggestive for GORD have increased AGOR and almost a quarter has DGE. However, there was no relation between GOR and GE. © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Gastric emptying; Gastro-oesophageal reflux; Cystic fibrosis; Children; Multichannel intraluminal impedance-pH monitoring; breath test
13
C-gastric emptying
Abbreviations: GOR, Gastro-oesophageal reflux; CF, Cystic fibrosis; GE, Gastric emptying; MII-pH, Multichannel intraluminal impedance-pH monitoring; GEBT, Gastric emptying breath test; AGOR, Acid gastro-oesophageal reflux; DGE, Delayed gastric emptying; GI, Gastrointestinal; GORD, Gastro-oesophageal reflux disease; NAGOR, Nnon-acid gastro-oesophageal reflux; NGE, Normal gastric emptying; RGE, Rapid gastric emptying; 99mTS, 99mTechnetium scintigraphy; 13 C-OBT, 13C-octanoic acid breath test; 13C-ABT, 13C-acetate breath test; PI, Pancreatic insufficiency; PS, Pancreatic sufficiency; BMI, Body mass index; FEV1, Forced expired volume at 1 s; PPI, Proton pump inhibitors; LOS, Lower oesophageal sphincter; MII, Multichannel intraluminal impedance; MII-GOR, Multichannel intraluminal impedance gastro-oesophageal reflux; MII-AGOR, Multichannel intraluminal impedance acid gastro-oesophageal reflux; MII-NAGOR, Multichannel intraluminal impedance non-acid gastro-oesophageal reflux; RI, Refluxindex; IRIS, Infra Red Isotope; t1/2-GE, Gastric half emptying time; P90, Percentile 90; P10, Percentile 10. ☆ Part of this work was presented as poster presentation and published as abstract in the Journal of Cystic Fibrosis at the: 32nd European Cystic Fibrosis Conference, Brest, France, 2009 and 36th European Cystic Fibrosis Conference, Lissabon, Portugal, 2013. ⁎ Corresponding author at: Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, BE-1090 Brussels, Belgium. Tel.: + 32 24775780; fax: + 32 24775783. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.jcf.2015.12.015 1569-1993/© 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Please cite this article as: Hauser B, et al, Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/ 10.1016/j.jcf.2015.12.015
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1. Introduction Cystic fibrosis (CF) is an inherited disease affecting not only the lungs but also the entire digestive system. Gastrointestinal (GI) symptoms are the most important non-pulmonary manifestations of this disease. Gastro-oesophageal reflux (GOR) and GOR disease (GORD) are more frequent in adults and children with CF compared with healthy controls. Most GOR studies in patients with CF have been performed with pH-metry which measures only acid GOR (AGOR). Multichannel intraluminal impedance-pH monitoring (MII-pH) measures AGOR and non-acid GOR (NAGOR) which can be both increased in CF. Delayed gastric emptying (DGE) can contribute to GOR. DGE, normal GE (NGE) as well as rapid GE (RGE) have been reported in adults and children with CF [1–3]. The “gold standard” to measure gastric emptying (GE) is 99m Technetium scintigraphy (99mTS) which is associated with a radiation exposure [4]. For this reason, alternative nonradioactive methods using the stable isotope 13C have been developed. The 13C-octanoic acid breath test (13C-OBT) to measure GE of solids and the 13C-acetate breath test (13C-ABT) to measure GE of liquids were developed [5,6]. We have recently validated the 13C-ABT and the 13C-OBT against 99mTS in children with upper GI symptoms and established normal values for the GE of liquids and solids in healthy children measured with the 13C-ABT and the 13C-OBT (submitted).
To the best of our knowledge, there is only one study in adults (n = 20) and one study in children (n = 15) with CF where MII-pH and GE assessment were both performed in the same patients. Both studies showed an abnormal MII-pH and DGE in 67% and 33% of the adults, and in 54.8% and 33.3% of the children, respectively, but found no correlation between DGE and increased GOR except for a subgroup of adults with DGE and increased acidic duodenogastro-oesophageal reflux [7,8]. The aim of this study was to investigate in children with CF (1) GOR measured with MII-pH, (2) GE measured with GE breath test (GEBT) and (3) the relationship between GOR and GE. 2. Material and methods 2.1. Subjects This prospective study was performed in 56 children with CF. MII-pH was performed in 28 children selected on the basis of GI symptoms (belching, epigastric pain, heartburn, regurgitation, vomiting) and/or respiratory symptoms (signs of unexplained respiratory evolution despite maximal therapy) suggestive for GORD. A GEBT was also performed in these patients (group 1). GEBT alone was performed in another 28 children with CF with/without GOR symptoms selected on the basis that they agreed to undergo a GEBT but not MII-pH (group 2) (Table 1). The diagnosis of CF had been made on the
Table 1 Group 1 (multichannel intraluminal impedance-pH monitoring and gastric emptying breath test) and group 2 (gastric emptying breath test alone): patient characteristics.
Age (years) Gender (boys/girls) (n) Pancreas function (PI/PS) (n) Genotype F508del homozygous (n) F508del heterozygous (n) Others (n) Unknown (n) Weight (kg) Weight SDS (Z-score) Height (cm) Height SDS (Z-score) BMI (kg/m²) BMI SDS (Z-score) FEV1% predicted Colonisation with Pseudomonas aeruginosa (n) Staphylococcus aureus (n) Upper GI symptoms (n) Meconium ileus (n) Intake PPI (n) Intake prokinetics (n) Intake azithromycin (n) Intake insulin (n) Intake laxatifs (n) Intake ursodeoxycholic acid (n)
Group 1 (MII-pH + GEBT) (n = 28)
Group 2 (GEBT alone) (n = 28)
p group 1 versus group 2
4.4 (1–17) 14–14 21–7
9.0 (4–14) 18–10 17–11
0.001 0.280 0.252 0.884
11 7 5 5 16.0 (6.2–55.0) − 1.02 (− 3.15; 1.26) 107.0 (61.0–159.4) − 0.66 (− 6.94; 2.23) 15.0 (11.5–22.3) − 1.06 (− 3.70; 2.97) 95.0 (39.2–129.6)
9 9 4 6 27.5 (16.0–53.0) − 0.47 (− 2.60; 1.89) 132.5 (105.0–175.0) − 0.12 (− 2.15; 2.99) 15.6 (13.2–21.0) − 0.50 (− 2.11; 2.04) 97.5 (37.8–123.1)
0.001 0.007 0.001 0.029 0.252 0.188 0.487
7 18 14 4 12 8 2 2 14 7
8 23 10 5 5 5 2 1 15 5
0.763 0.131 0.280 0.716 0.042 0.342 1.000 0.553 0.789 0.515
Legend: MII-pH: multichannel intraluminal impedance-pH monitoring; GEBT: gastric emptying breath test; PI: pancreatic insufficiency; PS: pancreatic sufficiency; BMI: body mass index; FEV1: forced expired volume in 1 s; GI: gastrointestinal; PPI: proton pump inhibitors. Please cite this article as: Hauser B, et al, Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/ 10.1016/j.jcf.2015.12.015
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basis of an abnormal sweat test and genotype determination. All subjects were in stable clinical condition at the moment of the investigations and stopped medication known to affect GI motility and gastric acid secretion at least 2 weeks before MII-pH and GEBT were performed. We analysed if one of the following patient characteristics were related to the results of MII-pH and GEBT: age (years), gender (boy, girl), pancreatic exocrine function (pancreatic insufficiency (PI) and pancreatic sufficiency (PS)), genotype (F508del homozygous, F508del heterozygous, other mutations and unknown mutations), weight (kg) and SDS (Z-score), height (cm) and SDS (Z-score), body mass index (BMI) (kg/cm²) and SDS (Z-score), forced expired volume at 1 s (FEV1% predicted), colonisation with Pseudomonas aeruginosa and Staphylococcus aureus, upper GI symptoms (anorexia, belching, bloating, early satiety, epigastric pain, heartburn, nausea, postprandial fullness, regurgitation, vomiting), history of meconium ileus, intake of proton pump inhibitors (PPI), intake of prokinetics, intake of azitromycine, intake of insulin, intake of laxatifs and intake of ursodeoxycholic acid. The children were recruited at the CF clinic of the Universitair Ziekenhuis Brussel, Brussels, Belgium. The local Ethics Committee approved the protocol. Written informed consent was obtained from the parents, and if possible from the children themselves. 2.2. GOR monitoring with MII-pH GOR was measured using ambulatory 24 h MII-pH with a 2.1 mm diameter catheter that comprises 6 electrode pairs to measure oesophageal intraluminal impedance and 2 antimony pH sensors to measure oesophageal and gastric pH (Sleuth, Sandhill Scientific Inc, Highlands Ranch, CO, USA) according to an ESPGHAN EURO-PIG standard protocol [9]. Multichannel intraluminal impedance (MII) GOR (MII-GOR) was defined as a progressing drop in impedance to b 50% of the baseline values starting distally at the lower oesophageal sphincter (LOS) and progressing to at least the next 2 more proximal measuring segments in the oral direction. The MII-GOR was classified as MII-AGOR (pH b 4) or MII-NAGOR (pH ≥ 4) according to the corresponding pH change. The number of MII-AGOR episodes, number of MII-NAGOR episodes and the total number of MII-GOR episodes were calculated. The total 24 h oesophageal acid exposure or refluxindex (RI), corresponding to the percentage of time that the oesophageal pH was below 4, was calculated with the pH-recording independently from the MII-recording. MII-pH results were considered abnormal if values of RI were N 5% corresponding to increased pH-AGOR [10]. 2.3. Test meals for GEBT GEBT tests were performed the day after the MII-pH. According to the age and preference of the children, a standardised liquid or solid test meal was administered in the morning after an overnight fast. The MII-pH catheter was removed in the morning before the GEBT was started. Concerning the GE of liquids, the children ingested within 5 to 10 min a standardised liquid test meal consisting of 200 ml
3
milk with a strawberry taste and a caloric content of 112 kcal (INZA Drink®). The milk-drink was labelled with 13C-acetate related to body weight (weight b 10 kg: 20 mg, weight 10– 30 kg: 50 mg, weight N 30 kg: 100 mg) (Eurisotop, SaintAubain, France). Concerning the GE of solids, the children ingested within 10 to 15 min a standardised solid test meal consisting of 1 pancake (17 g wheat flour, 7 g sugar, 1 egg white, 1 egg yolk labelled with 50 μL 13C-octanoic acid (Eurisotop SA, Saint Aubain, France), 40 ml semi-skimmed milk). This pancake batter was baked with 5 g margarine. For consumption, 5 g of sugar was added as sweetener and 100 ml of water was given as drink. The total caloric content was 230 kcal. During the GEBT no drinking or eating and only limited physical activities were allowed. 2.4. GEBT with
13
C-ABT and
13
C-OBT
Breath samples were collected before, every 5 min for the first 40 min and every 10 min for the following 140 min after ingestion of the liquid test meal. Breath samples were collected before and every 15 min for the following 240 min after ingestion of the solid test meal. Breath samples were collected in Infra Red Isotope (IRIS) breath sample aluminium bags with a content of 100 ml connected with a mouthpiece with internal rebreath stop valve. Breath samples were analysed for 13 CO2-enrichment using non dispersive infrared spectrometry with the IRIS-lab-infrared- 13C-isotope-analyser. Non-linear regression analysis of the curve that best fits the cumulative 13 CO2 excretion curve and the 13CO2 excretion by time curve was performed according to the methods described by Ghoos et al. [5] using the IRIS-software “GE2.DEM” for Microsoft Windows (Wagner Analysen Technik, Bremen, Germany). It allowed the calculation of the gastric half emptying time (t1/2-GE) which is the time on which half of the dose of 13 CO2 is excreted of the cumulative 13 CO2 when time is infinite. We defined DGE as t1/2-GE N percentile 90 (P90) and RGE as t1/2-GE b percentile 10 (P10) according to normal values established in healthy children (submitted). 2.5. Statistical analysis Results are presented as medians and ranges. Comparison between groups was done using the Mann-Whitney U test, t-test and ANOVA test when appropriate. Pearson chi-square test and Fisher's exact test were used to compare categorical variables. P b 0.05 was considered statistically significant. Statistics were calculated using the statistical program SPSS version 21.0 for Windows. 3. Results 3.1. Subjects The patients in group 1 were younger than in group 2 so that their weight and height was also lower but BMI was comparable. There were more patients taking PPI in group 1
Please cite this article as: Hauser B, et al, Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/ 10.1016/j.jcf.2015.12.015
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compared to group 2. There were no statistically significant differences between both groups for the other patient characteristics (Table 1).
pH-AGOR in comparison with the group with normal pHAGOR. There were no statistically significant differences between the groups with normal and increased pH-AGOR for the other patient characteristics (Table 2).
3.2. GOR monitoring with MII-pH 3.3. GEBT with Increased pH-AGOR was detected in 13/28 children (46.4%). All MII-pH parameters (number of MII-AGOR episodes, number of MII-NAGOR episodes, total number of MII-GOR episodes and RI) were higher in the group with increased pH-AGOR in comparison with the group with normal pH-AGOR. Of the total number of MII-GOR episodes, 2/3 were MII-AGOR episodes and 1/3 were MII-NAGOR episodes (p = 0.0001). There was no statistically significant difference for t1/2-GE of solids and liquids between the groups with increased and normal pH-AGOR. There were fewer patients with meconium ileus and a strong trend for more girls and more patients with upper GI symptoms in the group with increased
13
C-ABT and
13
C-OBT
DGE was found in 6/28 (21.4%) of the children from group 1 and in 0/28 (0%) of the children from group 2 but there were more children with NGE and RGE in group 2 in comparison with group 1: NGE in 20/28 (71.4%) from group 1 versus 23/28 (82.1%) from group 2 and RGE in 2/28 (7.2%) from group 1 versus 5/28 (17.9%) from group 2 (p = 0.024). DGE, RGE and NGE were present in respectively 6/56 (10.7%), 7/56 (12.5%) and 43/56 (76.8%) of all the children that underwent a GEBT (Table 3). Children with RGE were older so that their height was higher and there was a strong trend for a higher weight but their BMI was comparable in comparison with children with
Table 2 Group 1 (multichannel intraluminal impedance-pH monitoring and gastric emptying breath test): multiple intraluminal impedance-pH monitoring parameters, gastric emptying breath test parameters and patient characteristics of the group with normal multiple intraluminal impedance-pH monitoring and the group with abnormal multiple intraluminal impedance-pH monitoring.
Refluxindex (%) MII-AGOR episodes (n) MII-AGOR episodes (%) MII-NAGOR episodes (n) MII-NAGOR episodes (%) MII-GOR episodes (n) t1/2-GE solids (min) t1/2-GE liquids (min) Age (years) Gender (boys/girls) (n) Pancreas function (PI/PS) (n) Genotype F508del homozygous (n) F508del heterozygous (n) Others (n) Unknown (n) Weight (kg) Weight SDS (Z-score) Height (cm) Height SDS (Z-score) BMI (kg/m²) BMI SDS (Z-score) FEV1% predicted Colonisation with Pseudomonas aeruginosa (n) Staphylococcus aureus (n) Upper GI symptoms (n) Meconium ileus (n) Intake PPI (n) Intake prokinetics (n) Intake azithromycin (n) Intake insulin (n) Intake laxatifs (n) Intake ursodeoxycholic acid (n)
Group normal MII-pH (n = 15)
Group abnormal MII-pH (n = 13)
p group normal MII-pH versus group abnormal MII-pH
2.2 (0.1–4.0) 14 (2–33) 69.0 (28.6–95.0) 6 (1–22) 27.6 (5.0–71.4) 20 (7–52) 138 (88–528) 95 (83–106) 4 (2–9) 10–5 10–5
10.4 (6.9–29.0) 29 (8–83) 63.6 (30.5–98.5) 16 (1–64) 32.0 (1.5–69.5) 51 (22–112) 165 (115–911) 79 (66–134) 6 (1–17) 4–9 11–2
0.0010 0.004 0.593 0.015 0.560 0.001 0.420 0.564 0.216 0.058 0.274 0.091
6 2 2 5 15.9 (9.6–26.8) − 1.06 (− 3.15; 0.27) 105.0 (75.0–131.0) − 0.49 (− 6.94; 1.67) 14.5 (11.5–21.3) − 0.12 (− 3.70; 2.97) 97.4 (39.2–129.6)
5 5 3 0 20.0 (6.2–55.0) − 0.99 (− 1.87; 1.26) 118.5 (61.0–159.4) − 0.73 (− 2.46; 2.23) 15.3 (12.7–22.3) − 0.63 (− 3.29; 0.52) 94.9 (49.6–125.6)
0.104 0.277 0.337 0.541 0.204 0.976 0.593
2 10 5 4 5 3 0 0 7 3
5 8 9 0 7 5 2 2 7 4
0.126 0.778 0.058 0.044 0.274 0.281 0.115 0.115 0.705 0.512
Legend: MII-pH: multichannel intraluminal impedance-pH monitoring; MII-AGOR: multichannel intraluminal impedance acid gastro-oesophageal reflux; MII-NAGOR: multichannel intraluminal impedance non-acid gastro-oesophageal reflux; MII-GOR: multichannel intraluminal impedance gastro-oesophageal reflux; t1/2-GE: gastric half emptying time; PI: pancreatic insufficiency; PS: pancreatic sufficiency; BMI: body mass index; FEV1: forced expired volume in 1 s; GI: gastrointestinal; PPI: proton pump inhibitors. Please cite this article as: Hauser B, et al, Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/ 10.1016/j.jcf.2015.12.015
B. Hauser et al. / Journal of Cystic Fibrosis xx (2015) xxx–xxx Table 3 Group 1 (multichannel intraluminal impedance-pH monitoring and gastric emptying breath test), group 2 (gastric emptying breath test alone) and group 1 + 2: gastric emptying results.
DGE NGE RGE
Group 1 (MII-pH + GEBT) (n = 28)
Group 2 (GEBT alone) (n = 28)
Group 1 + 2 (all GEBT) (n = 56)
6 (21.4%) 20 (71.4%) 2 (7.2%)
0 (0%) 23 (82.1%) 5 (17.9%)
6 (10.7%) 43 (76.8%) 7 (12.5%)
Legend: MII-pH: multichannel intraluminal impedance-pH monitoring; GEBT: gastric emptying breath test; DGE: delayed gastric emptying; NGE: normal gastric emptying; RGE: rapid gastric emptying; p of group 1 versus group 2 = 0.024.
DGE. There were no statistically significant differences between the groups with an NGE, DGE and RGE for the other patient characteristics (Table 4).
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3.4. Relation between GE and GOR DGE was present in 3/13 (23.1%) of the children with increased pH-AGOR as well as in 3/15 (20.0%) of the children with normal pH-AGOR (p = 0.393) (Table 5A). There were no statistically significant differences in MII-pH parameters between patients with NGE, DGE and RGE (Table 5B). In accordance, there were no statistically significant correlations between any of the MII-pH parameters and rate of GE (Table 5C). 4. Discussion In the present study we assessed GOR with MII-pH and GE with 13C-ABT or 13C-OBT in children with CF and showed that I) 46.4% have increased pH-AGOR and 21.4% have DGE in a group of patients selected on the basis of GI and/or
Table 4 Group 1 (multichannel intraluminal impedance-pH monitoring and gastric emptying breath test) + group 2 (gastric emptying breath test alone): gastric emptying parameters and patient characteristics of group normal gastric emptying, group delayed gastric emptying and group rapid gastric emptying. Group NGE (n = 43)
Group DGE (n = 6)
Group RGE (n = 7)
p NGE vs DGE NGE vs RGE DGE vs RGE
t1/2-GE solids (min)
148 (102–239)
388 (292–911)
92 (83–110)
0.000 0.078 0.000
t1/2-GE liquids (min) Age (years)
81 (66–106) 7.0 (1–17)
134 5.1 (1–9)
9.0 (4–14)
Gender (boys/girls) (n) Pancreas function (PI/PS) (n) Genotype F508del homozygous (n) F508del heterozygous (n) Others (n) Unknown (n) Weight (kg) Weight SDS (Z-score)
23–20 29–14
3–3 4–2
6–1 5–2
0.127 0.249 0.043 0.260 0.976 0.874
15 11 8 9 21.0 (6.2–55.0) − 0.62 (− 2.60; 1.89)
3 2 0 1 15.0 (9.6–38.0) − 1.41 (− 3.15; 1.26)
2 3 1 1 27.0 (16.0–53.0) − 0.59 (− 1.36; 1.16)
Height (cm) Height SDS (Z-score)
123.0 (61.0–175.0) − 0.49 (− 2.46; 2.99)
99.0 (75.0–147.0) − 0.93 (− 6.94; 2.23)
140.0 (105.0–166.0) − 0.13 (− 1.72; 1.39)
BMI (kg/m²) BMI SDS (Z-score)
15.3 (12.6–22.3) − 0.73 (− 3.29; 2.04)
16.2 (11.5–21.3) − 0.46 (− 3.70; 2.97)
15.4 (13.8–19.2) − 0.95 (− 1.65; 0.06)
FEV1% predicted
95.0 (37.8–129.6)
97.0 (39.2–125.6)
102.0 (77.2–110.5)
Colonisation with Pseudomonas aeruginosa (n) Staphylococcus aureus (n) Upper GI symptoms (n) Meconium ileus (n) Intake PPI (n) Intake prokinetics (n) Intake azithromycin (n) Intake insulin (n) Intake laxatifs (n) Intake ursodeoxycholic acid (n)
13 32 16 7 14 9 4 2 20 10
0 3 3 0 2 2 0 0 4 0
2 6 5 2 1 2 0 1 5 2
0.177/0.174 0.238/0.486 0.057/0.117 0.07/0.085 0.165/0.534 0.017/0.072 0.588/0.500 0.707/0.870 0.881/0.666 0.735 0.804 0.656 0.291 0.327 0.221 0.375 0.613 0.747 0.521 0.477 0.351 0.380
Legend: NGE: normal GE; DGE: delayed GE; RGE: rapid GE; t1/2-GE: gastric half emptying time; PI: pancreatic insufficiency; PS: pancreatic sufficiency; BMI: body mass index; FEV1: forced expired volume in 1 s; GI: gastrointestinal; PPI: proton pump inhibitors. Please cite this article as: Hauser B, et al, Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/ 10.1016/j.jcf.2015.12.015
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Table 5 Relation between gastric emptying and gastro-oesophageal reflux. 5A. Relation between results of MII-pH and GEBT
Abnormal MII-pH (n = 13)
Normal MII-pH (n = 15)
DGE (n = 6) NGE (n = 20) RGE (n = 2)
3 (10.7%) 10 (35.7%) 0 (0%)
3 (10.7%) 10 (35.7%) 2 (7.2%)
Legend 5A: MII-pH: multichannel intraluminal impedance-pH monitoring; GEBT: gastric emptying breath test; DGE: delayed gastric emptying; NGE: normal gastric emptying; RGE: rapid gastric emptying; p of group abnormal MII-pH versus group normal MII-pH = 0.393. 5B. Relation between results of GEBT and GOR episodes
Group NGE (n = 20)
Group DGE (n = 6)
Group RGE (n = 2)
p
Refluxindex (%) MII-AGOR episodes (n) MII-AGOR episodes (%) MII-NAGOR episodes (n) MII-NAGOR episodes (%) MII-GOR episodes (n)
5.5 (0.8–13.9) 23 (8–66) 63.6 (30.5–98.5) 10 (1–64) 32.0 (1.5–69.5) 35 (14–95)
4.8 (0.1–29.0) 13 (2–83) 71.4 (28.6–78.9) 10 (2–29) 28.7 (21.1–71.4) 21 (7–112)
3.2 (2.3–4.0) 12 (9–15) 67.8 (45.5–90.0) 10 (1–18) 34.8 (10.0–59.5) 22 (10–33)
0.861 0.356 0.972 0.797 0.957 0.357
Legend 5B: GEBT: gastric emptying breath test; DGE: delayed gastric emptying; NGE: normal gastric emptying; RGE: rapid gastric emptying; MII-AGOR: multichannel intraluminal impedance acid gastro-oesophageal reflux; MII-NAGOR: multichannel intraluminal impedance non-acid gastro-oesophageal reflux; MII-GOR: multichannel intraluminal impedance gastro-oesophageal reflux. 5C. Correlation between results of GE and GOR episodes
t1/2-GE solids (min) (n = 23)
Refluxindex (%) MII-AGOR episodes (n) MII-NAGOR episodes (n) MII-GOR episodes (n)
r r r r
= = = =
− 0.280; p − 0.365; p − 0.257; p − 0.305; p
= = = =
0.207 0.095 0.249 0.168
t1/2-GE liquids (min) (n = 5) r r r r
= = = =
0.319; p = 0.601 − 0.144; p = 0.856 − 0.443; p = 0.557 − 0.197; p = 0.803
Legend 5C: t1/2-GE: gastric half emptying time; MII-AGOR: multichannel intraluminal impedance acid gastro-oesophageal reflux; MII-NAGOR: multichannel intraluminal impedance non-acid gastro-oesophageal reflux; MII-GOR: multichannel intraluminal impedance gastro-oesophageal reflux.
respiratory symptoms suggestive for GORD who agreed to undergo a MII-pH and GEBT, II) none has DGE in a group of patients with/without GOR symptoms selected on the basis that they agreed to undergo a GEBT but not MII-pH, III) 10.7% have DGE and 12.5% have RGE in the whole group, IV) there is no relationship between increased pH-AGOR and DGE, and V) there are no correlations between any of the GORparameters and GE-rate. Feigelson et al. reported in 1975 for the first time increased GOR in adults and children with CF [11]. Meanwhile, more studies have looked at GOR in adults and children with CF. Most studies have used pH-metry which only measures pHAGOR. Several studies using MII-pH which measures pHAGOR, MII-AGOR, MII-NAGOR and MII-GOR have been performed more recently. All the studies have shown an increased pH-AGOR/MII-GOR that varies between 19.2% and 100% of adults and children with CF (Supplemental Table S1). We found in the present study an increased pH-AGOR in 46.4% of children with CF with symptoms suggestive for GORD. The frequency of increased pH-AGOR/MII-GOR is highly variable across the different studies, probably due to patient selection (different ages, different stages of disease, with/without GOR symptoms) and different normal values that were used (Supplemental Table S1). In the present study, it was impossible to determine whether the number of MII-AGOR, MII-NAGOR and MII-GOR episodes was increased as there are no normal values in children. Wenzl et al. proposed to
define arbitrarily an abnormal MII-pH as N 70 MII-GOR episodes in 24 h in patients ≥ 1 year and N 100 MII-GOR episodes in patients b 1 year [9]. If we would apply these normal values to the present study, only 2 patients would have an abnormal MII-pH. Studies using MII-pH have systematically shown a predominance of MII-AGOR over MII-NAGOR in CF [7,8,12–15], what is confirmed by our data. This might be due to an increased gastric acid secretion [16] and decreased gastric neutralisation due to reduced bicarbonate pancreatic secretion in CF [17]. There were fewer patients with meconium ileus and a strong trend for more girls and more patients with upper gastrointestinal symptoms in the group with increased pH-AGOR. Several studies showed that there was no difference in age, gender, pancreatic function, genotype, nutritional status, lung function, Pseudomonas colonisation, meconium ileus and diabetes between patients with CF with abnormal or normal pH-metry / MII-pH [7,8,13,18,19]. Except for meconium ileus, all findings are confirmed by our data. Increased GOR can cause typical oesophageal (heartburn, regurgitation, vomiting) and extra-oesophageal (cough, hoarseness, wheezing) symptoms but can also occur silently in patients with CF [1,2]. The reported incidence of typical GOR symptoms in patients with CF varies between 20.6% and 39% with one exception reporting 94% (adults only) [20–23]. The number of patients with CF with increased pH-AGOR/ MIIGOR that presents with clinical GOR symptoms varies between
Please cite this article as: Hauser B, et al, Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/ 10.1016/j.jcf.2015.12.015
B. Hauser et al. / Journal of Cystic Fibrosis xx (2015) xxx–xxx
0% and 100% depending on the study population selection (Supplemental Table S1). In the present study, 8/13 (61.5%) of the children with CF with increased pH-AGOR reported at least 1 typical GOR symptom in comparison with 3/15 (20%) of the children with CF with normal pH-AGOR (p = 0.025). NGE, DGE and RGE have been described in children and adults with CF (Supplemental Table S2). In the present study, we found DGE in 21.4% of children with CF with symptoms suggestive for GORD who agreed to undergo a MII-pH and GEBT but no DGE in the children with CF with/without GOR symptoms who agreed to undergo a GEBT but not MII-pH. The children in the first group were younger and had historically been taking more often PPI in comparison with the children from the second group. This is probably due to the fact that those children were more often believed to have GORD. For the whole group, we found DGE in 10.7% and RGE in 12.5%. This could be expected as we defined DGE as t1/2-GE N P90 and RGE as t1/2-GE b P10 according to normal values established in healthy children (submitted). DGE for solids, solid/ liquid meal and liquids was reported respectively in 72.7%, 89.7% and 33.3% of children with CF [8,24,25]. DGE for solids and liquids was found respectively between 5.8% and 97.0% and between 0% and 67.0% of adults with CF [7,26– 29]. RGE for liquids or solids was also found in 2.0% of adults with CF [26–27]. Pauwels et al. found DGE in 11/33 (33.3%) adults with CF in a study where MII-pH and 13C-OBT were performed at the same time, as we did [7]. They defined DGE as t1/2-GE N 75 min but this value corresponds to P75 of normal values for t1/2-GE in healthy adult volunteers [5]. If we would define DGE as t1/2-GE N P75 in our study, 18/56 (32.1%) of the children with CF would have a DGE which is comparable with the results from Pauwels et al. [7]. The diversity of results found in the studies that examined GE may be explained by different factors. Patients of different ages and stages of disease were included. Different diagnostic methods (13C-OBT, 13C-ABT, magnet-based motility tracking system, marker dilution technique, scintigraphy, ultrasound, wireless motility capsule), protocols (fasting or test meal, test meal type, duration test) and normal values for GE were used (Supplemental Table S2). In the present study, children with RGE were older in comparison with children with DGE. There were however no significant differences for gender, pancreas function, genotype, lung function, colonisation with P. aeruginosa and S. aureus, constipation, diabetes and liver disease between the groups with an NGE, DGE or RGE (Table 4), confirming data from literature [7,8,25,27,30]. DGE may cause symptoms such as anorexia, belching, bloating, early satiety, epigastric pain, nausea, postprandial fullness and vomiting. There is however a poor correlation between clinical manifestations and abnormal GE, and the most important symptoms (bloating, early satiety, epigastric pain, nausea and vomiting) are variably present in patients with CF [26,27]. In the present study, not only 3/6 (50.0%) of patients with DGE but also 5/7 (71.4%) of patients with RGE reported at least 1 GI symptom of abnormal GE. Bodet-Milin et al. showed that 17/29 (58.0%) of patients with CF with DGE had
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GI symptoms [27]. Bentur et al. showed that 10/13 (76.9%) of the patients with CF with an abnormal myoelectrical activity of the stomach had GI complaints [25]. Increased GOR in patients with CF is most likely promoted by several factors. Increased number of transient LOS relaxations, reduced LOS pressure, and DGE have been proposed as primary mechanisms associated with GOR in CF. Secondary pathophysiological mechanism like chest physiotherapy and cough have also been suggested to provoke GOR in patients with CF [1–3,23,29]. Blondeau et al. showed however that GOR occurs mostly as a primary phenomenon and is not secondary to cough in patients with CF [12,13]. We showed that DGE was not associated with increased pH-AGOR, that there was no difference in MII-pH parameters between patients with NGE, DGE and RGE, and that there were no correlations between the MII-pH parameters and the rate of GE (Table 5A–C). We could not find any relation between GE rate and acid as well as and non-acid GOR in children with CF and symptoms suggestive for GORD. We can confirm the data of Pauwels et al. showing the absence of correlation between MII-pH parameters and GE rate in adults with CF [7]. Caldaro et al. also found no correlation between GE and GOR events that reach the proximal oesophagus and oesophagitis in children with CF [8]. This study has several limitations. Firstly, there is a possible lack of power as no power calculation was performed. Participation to the study was proposed to the population of +/− 80 children with CF in our centre. Secondly, there are some differences between groups 1 and 2 as group 1 includes children who agreed to undergo a MII-pH and GEBT whilst the children in group 2 refused the MII-pH but accepted the GEBT. Retrospectively, children from group 1 presented more symptoms suggesting GORD than those in group 2. Moreover, the only statistical significant differences between patients of groups 1 and 2 were that patients in group 1 were younger and more were taking PPI (Table 1). We speculate that the symptoms of the patients in group 2 were less severe than in group 1, since more children in group 1 were taking PPI. As a consequence, the increased pH-AGOR and DGE in group 1 cannot be extrapolated to the general CF population. In conclusion, we found that in a group of children with CF with symptoms suggestive for GORD who agreed to undergo a MII-pH and GEBT, 46.4% have increased pH-AGOR and 21.4% have DGE but there was no relationship between pH-AGOR and DGE. On the contrary, we found no DGE in a group of children with CF with/without GOR symptoms who agreed to undergo a GEBT but no MII-pH. We finally found 10.7% DGE and 12.5% RGE in the whole group of children with CF which could be expected as DGE was defined as t1/2GE N P90 and RGE was defined as t1/2-GE b P10. Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.jcf.2015.12.015. Conflict of interest statement Anne Malfroot reports grants from Medi Pharma, nonfinancial support from ABBOTT, non-financial support from
Please cite this article as: Hauser B, et al, Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/ 10.1016/j.jcf.2015.12.015
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GILEAD, non-financial support from Novartis, non-financial support from FOREST, and other forms of support from PTC Therapeutics GmbH-Switserland but without conflicts of interest related to this work. Elke De Wachter reports grants from Novartis, grants from Meda Pharma, non-financial support from Abbott, non-financial support from Gilead, nonfinancial support from Novartis, and non-financial support from Forest but without conflicts of interest related to this work. Yvan Vandenplas is consultant for Biocodex, ASPEN, Kabrita and United Pharmaceuticals but without conflicts of interest related to this work. The other authors have no conflicts of interest to report. Acknowledgements This study was partially funded by the “Willy Gepts Fonds” from the Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium. This scientific academic fund had no role in the study design, in the collection, analysis and interpretation of date, in the writing of the manuscript and in the decision to submit the manuscript for publication. References [1] Mousa HM, Woodley FW. Gastroesophageal reflux in cystic fibrosis: current understandings of mechanisms and management. Curr Gastroenterol Rep 2012;14:226–35. [2] Haller W, Ledder O, Lewindon PJ, Couper R, Gaskin KJ, Oliver M. Cystic fibrosis: an update for clinicians. Part 1: nutrition and gastrointestinal complications. J Gastroenterol Hepatol 2014;29:1344–55. [3] Kelly T, Buxbaum J. Gastrointestinal manifestations of cystic fibrosis. Dig Dis Sci Feb 4 2015 [Epub ahead of print]. [4] Abell TL, Camilleri M, Donohoe K, Hasler WL, Lin HC, Maurer AH, et al. Consensus recommendations for gastric emptying scintigraphy: a joint report of the Society of Nuclear Medicine and the American Neurogastroenterology and Motility Society. Am J Gastroenterol 2008; 103:753–63. [5] Ghoos YF, Maes BD, Geypens BJ, Mys G, Hiele MI, Rutgeers PJ, et al. Measurement of gastric emptying rate of solids by means of carbonlabelled octanoic acid breath test. Gastroenterology 1993;104:1640–7. [6] Braden B, Adams S, Duan LP, Orth KH, Maul FD, Lembke B, et al. The 13C-acetate breath test accurately reflects gastric emptying of liquids in both liquid and semisolid test meals. Gastroenterology 1995;108: 1048–55. [7] Pauwels A, Blondeau K, Mertens V, Farre R, Verbeke K, Dupont LJ, et al. Gastric emptying and different types of reflux in adult patients with cystic fibrosis. Aliment Pharmacol Ther 2011;34:799–807. [8] Caldaro T, Alghisi F, De Angelis P, Garganese MC, Rea F, Pizzoferro M, et al. Cystic fibrosis: a surgical matter ? J Pediatr Surg 2014;49:753–8. [9] Wenzl TG, Benninga MA, Loots CM, Salvatore S, Vandenplas Y, on behalf of the ESPGHAN EURO-PIG Working Group. Indications, methodology, and interpretation of combined esophageal impedance-pH monitoring in children: ESPGHAN EURO-PIG standard protocol. JPGN 2012;55:230–4. [10] Pilic D, Fröhlich T, Nöh F, Pappas A, Schmidt-Choudhury A, Köhler H, et al. Detection of gastroesophageal reflux in children using combined multichannel intraluminal impedance and pH measurement: data from the German Pediatric Impedance Group. J Pediatr 2011;158:650–4.
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Please cite this article as: Hauser B, et al, Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/ 10.1016/j.jcf.2015.12.015