Thoracoabdominal pressure gradient and gastroesophageal reflux: insights from lung transplant candidates

Thoracoabdominal pressure gradient and gastroesophageal reflux: insights from lung transplant... SUMMARY Advanced lung disease is associated with gastroesophageal reflux disease (GERD). The thoracoabdominal pressure gradient (TAPG) facilitates gastroesophageal reflux, but the effects of TAPG on gastroesophageal reflux in patients with pulmonary disease have not been well defined. Patients diagnosed with end-stage lung disease are expected to have the most extreme derangement in respiratory mechanics. The aim of this study is to explore the relationship between TAPG and reflux in lung transplant (LTx) candidates. We reviewed LTx recipients who underwent pretransplant esophageal high-resolution manometry and a 24-hour pH study. Patients were excluded if they were undergoing redo LTx, had manometric hiatal hernia, or had previously undergone foregut surgery. TAPG was defined as the intra-abdominal pressure minus the intrathoracic pressure during inspiration. Adjusted TAPG was calculated by the TAPG minus the resting lower esophageal sphincter (LES) pressure (LESP). Twenty-two patients with normal esophageal function tests (i.e., normal esophageal motility with neither manometric hiatal hernia nor pathological reflux on 24-hour pH monitoring) were selected as the pulmonary disease-free control group. In total, 204 patients underwent LTx between January 2015 and December 2016. Of these, 77 patients met inclusion criteria. We compared patients with obstructive lung disease (OLD, n = 33; 42.9%) and those with restrictive lung disease (RLD, n = 42; 54.5%). 2/77 patients (2.6%) had pulmonary arterial hypertension. GERD was more common in the RLD group than in the OLD group (24.2% vs. 47.6%, P = 0.038). TAPG was similar between the OLD group and the controls (14.2 vs. 15.3 mmHg, P = 0.850); however, patients in the RLD group had significantly higher TAPG than the controls (24.4 vs. 15.3 mmHg, P = 0.002). Although TAPG was not correlated with GERD, the adjusted TAPG correlated with reflux in all 77 patients with end-stage lung disease (DeMeester score, rs = 0.256, P = 0.024; total reflux time, rs = 0.259, P = 0.023; total number of reflux episodes, rs = 0.268, P = 0.018). Additionally, pathological reflux was seen in 59.1% of lung transplant candidates with adjusted TAPG greater than 0 mmHg (i.e., TAPG exceeding LESP); GERD was seen in 30.9% of patients who had an adjusted TAPG ≤ 0 mmHg. In summary, TAPG varies based on the underlying cause of lung disease. Higher adjusted TAPG increases pathological reflux, even if patients have normal antireflux anatomy and physiology (i.e., no hiatal hernia and manometrically normal LES function). Adjusted TAPG may provide further insights into the pathophysiology of GERD. INTRODUCTION Gastroesophageal reflux disease (GERD) has been associated with pulmonary disorders and is common in patients with advanced lung disease.1,2 However, the mechanism of the association between pulmonary disorder and gastroesophageal reflux remains to be elucidated. The stomach lies in a positive-pressure intra-abdominal position, while the esophagus is situated in the negative-pressure chest cavity. The pressure gradient between the abdominal and thoracic cavities is called the thoracoabdominal pressure gradient (TAPG). Because of the positive-pressure nature of the abdomen and the negative-pressure environment of the chest, there is a tendency for gastric fluid to flow from the stomach into the esophagus, and the TAPG determines the extent of this flow. The lower esophageal sphincter (LES) is the natural barrier against the retrograde flow of gastric juices. It has been suggested that physiologic changes in the thoracic cavity contribute to reflux because of increased TAPG across the LES.3-6 An elevated TAPG due to changes in pulmonary compliance or abdominal pressure is likely to further increase the magnitude of reflux. Increased body mass index (BMI) is known to result in greater intra-abdominal pressure; thus, individuals with above-average BMIs are more likely to experience GERD.7-9 However, few studies have focused on the role of intra-thoracic pressure as it relates to GERD. Patients diagnosed with end-stage lung disease are expected to have the most extreme derangement in respiratory mechanics, and these patients may help us understand how underlying lung disease is related to changes in TAPG. Furthermore, the respiratory mechanics of patients diagnosed with obstructive lung disease (OLD) (i.e., increased intrathoracic pressure during expiration), are opposite of those patients with a restrictive lung disease (RLD) (i.e., extreme negative pressure during inspiration). The aim of this study is to examine the association of GERD, TAPG, and underlying pulmonary disease in lung transplant candidates. MATERIALS AND METHODS Study population All patients who undergo lung transplant at our institution are prospectively entered into a database. We obtain complete foregut function testing on all patients whenever clinically possible. This includes high resolution manometry, 24-hour pH testing, endoscopy (performed by thoracic transplant surgeons) and gastric emptying studies. After Institutional Review Board approval (#PHXA-17-0172-71-18), we queried this database to identify patients who underwent pretransplant esophageal high-resolution manometry (HRM) and 24-hour pH study between January 2015 and December 2016. Esophageal HRM studies were reanalyzed using the Chicago Classification v 3.0.10 Underlying pulmonary disease was classified using United Network for Organ Sharing (UNOS) criteria: UNOS Criteria Group A, OLD; UNOS Criteria Group D, restrictive lung disease (RLD). We excluded patients who had undergone previous lung transplantation or foregut intervention, whose HRM or pH study was unavailable for reanalysis or was of poor quality, who had manometric hiatal hernia, or who were undergoing pH monitoring on acid suppression medications (proton pump inhibitors within 7 days or H2 receptor antagonists within 3 days before 24-hour pH study). We also established a control group comprising patients undergoing manometry and pH monitoring at our laboratory. Patients who had no history of pulmonary disease and healthy esophageal functional tests (i.e., normal esophageal motility without hiatal hernia on manometry, and nonpathological gastroesophageal reflux [DeMeester score ≤ 14.72] on 24-hour pH study) were used as control patients. From our database for esophageal functional testing, we identified patients who underwent both HRM and 24-hour pH study at our institution between January 2017 and December 2017. HRM studies were also reanalyzed using the Chicago Classification v 3.0.10 We excluded patients with known pulmonary lung disease, history of lung transplantation, history of foregut intervention, manometric hiatal hernia, any diagnosis of esophageal dysmotility (i.e., achalasia, esophagogastric junction [EGJ] outflow obstruction, diffuse esophageal spasm, jackhammer esophagus, absent contractility, ineffective esophageal motility, and fragmented peristalsis), poor-quality HRM or pH studies, pH monitoring with acid suppression medications, and abnormal DeMeester score (>14.72). High-resolution manometry HRM was performed with a 36-channel probe with circumferential sensors at 1-cm intervals (Sierra Scientific Instruments Inc., Los Angeles, CA). These studies were reanalyzed by a single author (TM) using Manoview software (Sierra Scientific Instruments Inc.). This author was blinded to patients’ 24-hour pH monitoring results. The esophageal pressure topography of ten 5-mL water swallows was diagnosed according to the Chicago Classification v 3.0.10 We also assessed EGJ barrier function against gastroesophageal reflux, using variables that have been previously established; namely, overall LES length (OL), abdominal LES length (AL), resting LES pressure (LESP),11 and LESP integral (LESPI).12 Thoracoabdominal pressure gradient Using the resting phase of the HRM studies, intra-abdominal pressure (AP), intrathoracic pressure (TP), and TAPG were assessed. AP was defined as the pressure 1 cm below the lower border of the crus at inspiration (referenced to atmospheric pressure). TP was defined as the pressure 5 cm above the upper border of the LES at inspiration (referenced to atmospheric pressure). This position is also the location of placement of a pH sensor for ambulatory pH monitoring. TAPG was calculated as AP minus TP (Fig. 1A). Fig. 1 View largeDownload slide Thoracoabdominal pressure gradient. (A) TAPG. (B) Adjusted TAPG. AP, intra-abdominal pressure; CD, crural diaphragm; E, expiration; I, inspiration; LES, lower esophageal sphincter; LESPap; LES pressure referred to AP; TAPG, thoracoabdominal pressure gradient; TP, intrathoracic pressure. Fig. 1 View largeDownload slide Thoracoabdominal pressure gradient. (A) TAPG. (B) Adjusted TAPG. AP, intra-abdominal pressure; CD, crural diaphragm; E, expiration; I, inspiration; LES, lower esophageal sphincter; LESPap; LES pressure referred to AP; TAPG, thoracoabdominal pressure gradient; TP, intrathoracic pressure. LES pressure (LESPap), referenced to the pressure at the same level of AP measurement (i.e., 1 cm below the lower border of the crus) was also assessed, and adjusted TAPG was calculated as TAPG minus LESPap (Fig. 1B). The cutoff value of adjusted TAPG to predict the risk of pathological reflux was set at >0 mmHg, according to a hypothesis previously suggested by Ayazi et al.4 Briefly, they described that gastroesophageal reflux may be induced if TAPG overcomes LESP, which works as a fundamental antireflux pressure. 24-hour pH monitoring Ambulatory esophageal pH monitoring was performed using either a catheter-based system (Digitrapper 400pH®; Medtronic, Minneapolis, MN) or a capsule-based system (Bravo®; Medtronic, Minneapolis, MN), according to previously described methods.13 Briefly, the catheter-based pH probe was passed transnasally and positioned 5 cm above the upper border of the LES (defined on manometry), while the capsule was passed transorally and positioned 6 cm above the gastroesophageal junction under endoscopic guidance. For the capsule-based system, the DeMeester score was calculated as the mean of the scores over 2 days. Statistical analysis All statistical analyses were performed using the SPSS version 22.0.0.0 (Armonk, NY). Chi-square test or Fisher exact test were used to compare categorical variables. The Mann-Whitney U test was used to compare continuous variables. Spearman's correlation was used to test the association between two ranked variables. Continuous variables were expressed as median and interquartile range. Statistical significance was set at P < 0.05. RESULTS In total, 204 patients underwent lung transplant during the study period. Of these, 174 patients underwent preoperative HRM. Patients with prior lung transplantation (n = 13), history of previous foregut intervention (n = 12), HRM unavailable for reanalysis or of poor quality (n = 33), manometric hiatal hernia (n = 34), and unavailable pH study (n = 5) were excluded. Not all patients had a complete workup as some were evaluated urgently or were too ill to undergo complete testing. The remaining 77 patients who met the study criteria made up the pulmonary disease group. Thirty-three patients had OLD, 42 patients had RLD, and 2 were diagnosed with pulmonary arterial hypertension. Abnormal DeMeester score (>14.72) was seen in 30/77 (39.0%) patients. The control group was composed of 22 patients who had no history of pulmonary disease, normal esophageal motility without manometric hiatal hernia, and nonpathological gastroesophageal reflux (i.e., DeMeester score ≤ 14.72) on 24-hour pH study. The demographics of the entire study population are summarized in Table 1. Age and sex were similar between patients with OLD and RLD. Patients in the pulmonary disease group were older than patients in the control group (64 vs. 52 years, P < 0.001). Table 1 Patient characteristics Variable All pulmonary disease OLD RLD Control n = 77 n = 33 n = 42 n = 22 Age, years 64.0 (57.0–68.0)*** 62.0 (57.0–68.0)** 65.5 (60.0–69.0)*** 52.0 (42.0–64.0) Sex, male:female† 44:33* 15:18 29:13** 6:16 BMI, kg/m2† 26.0 (22.9–29.6)** 24.0 (21.0–27.3)** 27.3 (24.3–30.6) 30.4 (25.1–38.7) DeMeester score 9.3 (2.9–21.5) 5.8 (1.8–14.7) 14.5 (4.0–28.0)** 4.9 (3.4–10.1) Abnormal DeMeester score (>14.72) 30 (39.0%)*** 8 (24.2%)* 20 (47.6%)*** 0 LES function LESP, mmHg 33.8 (24.4–40.6) 33.6 (23.3–41.5) 34.1 (26.8–40.0) 30.4 (25.1–38.7) Hypotensive LESP (<13 mmHg) 2 (2.6%) 1 (3.0%) 1 (2.4%) 0 LESPI, mmHg·s·cm 269.1 (151.0–467.3) 277.5 (111.6–744.7) 281.6 (178.0–360.5) 325.6 (55.8–480.1) OL, cm 2.9 (2.4–3.5) 2.7 (2.4–3.5) 3.0 (2.6–3.5) 3.1 (2.7–3.6) AL, cm 2.4 (2.1–2.8) 2.4 (2.1–2.8) 2.5 (2.1–2.9) 2.8 (2.3–3.2) HRM diagnosis Normal esophageal motility 32 (41.6%)*** 18 (54.5%)*** 14 (33.3%)*** 22 (100.0%) Esophageal dysmotility 45 (58.4%)*** 15 (45.5%)*** 28 (66.7%)*** 0 IEM 25 (32.5%) 8 (24.2%) 16 (38.1%) – Absent contractility† 7 (9.1%) 0 6 (14.3%) – Fragmented peristalsis 3 (3.9%) 1 (3.0%) 2 (4.8%) – EGJ outflow obstruction 8 (10.4%) 5 (15.2%) 3 (7.1%) – Achalasia 2 (2.6%) 1 (3.0%) 1 (2.4%) – Variable All pulmonary disease OLD RLD Control n = 77 n = 33 n = 42 n = 22 Age, years 64.0 (57.0–68.0)*** 62.0 (57.0–68.0)** 65.5 (60.0–69.0)*** 52.0 (42.0–64.0) Sex, male:female† 44:33* 15:18 29:13** 6:16 BMI, kg/m2† 26.0 (22.9–29.6)** 24.0 (21.0–27.3)** 27.3 (24.3–30.6) 30.4 (25.1–38.7) DeMeester score 9.3 (2.9–21.5) 5.8 (1.8–14.7) 14.5 (4.0–28.0)** 4.9 (3.4–10.1) Abnormal DeMeester score (>14.72) 30 (39.0%)*** 8 (24.2%)* 20 (47.6%)*** 0 LES function LESP, mmHg 33.8 (24.4–40.6) 33.6 (23.3–41.5) 34.1 (26.8–40.0) 30.4 (25.1–38.7) Hypotensive LESP (<13 mmHg) 2 (2.6%) 1 (3.0%) 1 (2.4%) 0 LESPI, mmHg·s·cm 269.1 (151.0–467.3) 277.5 (111.6–744.7) 281.6 (178.0–360.5) 325.6 (55.8–480.1) OL, cm 2.9 (2.4–3.5) 2.7 (2.4–3.5) 3.0 (2.6–3.5) 3.1 (2.7–3.6) AL, cm 2.4 (2.1–2.8) 2.4 (2.1–2.8) 2.5 (2.1–2.9) 2.8 (2.3–3.2) HRM diagnosis Normal esophageal motility 32 (41.6%)*** 18 (54.5%)*** 14 (33.3%)*** 22 (100.0%) Esophageal dysmotility 45 (58.4%)*** 15 (45.5%)*** 28 (66.7%)*** 0 IEM 25 (32.5%) 8 (24.2%) 16 (38.1%) – Absent contractility† 7 (9.1%) 0 6 (14.3%) – Fragmented peristalsis 3 (3.9%) 1 (3.0%) 2 (4.8%) – EGJ outflow obstruction 8 (10.4%) 5 (15.2%) 3 (7.1%) – Achalasia 2 (2.6%) 1 (3.0%) 1 (2.4%) – Continuous variables were expressed as the median (IQR)$$\|$$ Categorical variables were expressed as number (%). *P < 0.05, **P < 0.01, ***P < 0.001 compared with control group. †P < 0.05 compared between OLD and RLD. AL, abdominal LES length; BMI, body mass index; EGJ, esophagogastric junction, HRM, high-resolution manometry; IEM, ineffective esophageal motility; LES, lower esophageal sphincter; LESP, resting LES pressure; LESPI, LES pressure integral; OL, overall LES length; OLD, obstructive lung disease; RLD, restrictive lung disease. View Large Table 1 Patient characteristics Variable All pulmonary disease OLD RLD Control n = 77 n = 33 n = 42 n = 22 Age, years 64.0 (57.0–68.0)*** 62.0 (57.0–68.0)** 65.5 (60.0–69.0)*** 52.0 (42.0–64.0) Sex, male:female† 44:33* 15:18 29:13** 6:16 BMI, kg/m2† 26.0 (22.9–29.6)** 24.0 (21.0–27.3)** 27.3 (24.3–30.6) 30.4 (25.1–38.7) DeMeester score 9.3 (2.9–21.5) 5.8 (1.8–14.7) 14.5 (4.0–28.0)** 4.9 (3.4–10.1) Abnormal DeMeester score (>14.72) 30 (39.0%)*** 8 (24.2%)* 20 (47.6%)*** 0 LES function LESP, mmHg 33.8 (24.4–40.6) 33.6 (23.3–41.5) 34.1 (26.8–40.0) 30.4 (25.1–38.7) Hypotensive LESP (<13 mmHg) 2 (2.6%) 1 (3.0%) 1 (2.4%) 0 LESPI, mmHg·s·cm 269.1 (151.0–467.3) 277.5 (111.6–744.7) 281.6 (178.0–360.5) 325.6 (55.8–480.1) OL, cm 2.9 (2.4–3.5) 2.7 (2.4–3.5) 3.0 (2.6–3.5) 3.1 (2.7–3.6) AL, cm 2.4 (2.1–2.8) 2.4 (2.1–2.8) 2.5 (2.1–2.9) 2.8 (2.3–3.2) HRM diagnosis Normal esophageal motility 32 (41.6%)*** 18 (54.5%)*** 14 (33.3%)*** 22 (100.0%) Esophageal dysmotility 45 (58.4%)*** 15 (45.5%)*** 28 (66.7%)*** 0 IEM 25 (32.5%) 8 (24.2%) 16 (38.1%) – Absent contractility† 7 (9.1%) 0 6 (14.3%) – Fragmented peristalsis 3 (3.9%) 1 (3.0%) 2 (4.8%) – EGJ outflow obstruction 8 (10.4%) 5 (15.2%) 3 (7.1%) – Achalasia 2 (2.6%) 1 (3.0%) 1 (2.4%) – Variable All pulmonary disease OLD RLD Control n = 77 n = 33 n = 42 n = 22 Age, years 64.0 (57.0–68.0)*** 62.0 (57.0–68.0)** 65.5 (60.0–69.0)*** 52.0 (42.0–64.0) Sex, male:female† 44:33* 15:18 29:13** 6:16 BMI, kg/m2† 26.0 (22.9–29.6)** 24.0 (21.0–27.3)** 27.3 (24.3–30.6) 30.4 (25.1–38.7) DeMeester score 9.3 (2.9–21.5) 5.8 (1.8–14.7) 14.5 (4.0–28.0)** 4.9 (3.4–10.1) Abnormal DeMeester score (>14.72) 30 (39.0%)*** 8 (24.2%)* 20 (47.6%)*** 0 LES function LESP, mmHg 33.8 (24.4–40.6) 33.6 (23.3–41.5) 34.1 (26.8–40.0) 30.4 (25.1–38.7) Hypotensive LESP (<13 mmHg) 2 (2.6%) 1 (3.0%) 1 (2.4%) 0 LESPI, mmHg·s·cm 269.1 (151.0–467.3) 277.5 (111.6–744.7) 281.6 (178.0–360.5) 325.6 (55.8–480.1) OL, cm 2.9 (2.4–3.5) 2.7 (2.4–3.5) 3.0 (2.6–3.5) 3.1 (2.7–3.6) AL, cm 2.4 (2.1–2.8) 2.4 (2.1–2.8) 2.5 (2.1–2.9) 2.8 (2.3–3.2) HRM diagnosis Normal esophageal motility 32 (41.6%)*** 18 (54.5%)*** 14 (33.3%)*** 22 (100.0%) Esophageal dysmotility 45 (58.4%)*** 15 (45.5%)*** 28 (66.7%)*** 0 IEM 25 (32.5%) 8 (24.2%) 16 (38.1%) – Absent contractility† 7 (9.1%) 0 6 (14.3%) – Fragmented peristalsis 3 (3.9%) 1 (3.0%) 2 (4.8%) – EGJ outflow obstruction 8 (10.4%) 5 (15.2%) 3 (7.1%) – Achalasia 2 (2.6%) 1 (3.0%) 1 (2.4%) – Continuous variables were expressed as the median (IQR)$$\|$$ Categorical variables were expressed as number (%). *P < 0.05, **P < 0.01, ***P < 0.001 compared with control group. †P < 0.05 compared between OLD and RLD. AL, abdominal LES length; BMI, body mass index; EGJ, esophagogastric junction, HRM, high-resolution manometry; IEM, ineffective esophageal motility; LES, lower esophageal sphincter; LESP, resting LES pressure; LESPI, LES pressure integral; OL, overall LES length; OLD, obstructive lung disease; RLD, restrictive lung disease. View Large BMI was similar between RLD and control patients (27.3 vs 30.4 kg/m2, P = 0.070); however, patients in the OLD cohort had significantly lower BMI (24.0 kg/m2) than patients in the RLD and control groups (P = 0.010 and P = 0.001, respectively). HRM parameters for LES function and prevalence of esophageal dysmotility were similar between OLD and RLD groups. Underlying lung disease and TAPG Figure 2 depicts the differences in TP, AP, TAPG, and adjusted TAPG among the 3 groups. No difference in AP was observed across the 3 groups, although there was positive correlation between AP and BMI in the total cohort (rs = 0.436, P < 0.001). TP, TAPG, and adjusted TAPG did not differ between the OLD and control groups. TP in RLD group was more negative than in the control group (−7.5 vs. −0.7 mmHg, P = 0.002), and patients in the RLD group had greater TAPG and adjusted TAPG compared with patients in the control group (24.4 vs. 15.3 mmHg, P = 0.002; −1.7 vs. −9.5 mmHg, P = 0.043, respectively). Fig. 2 View largeDownload slide Underlying lung disease and thoracoabdominal pressure gradient. (A) TP in each group. More negative TP was seen in RLD group than both OLD and control groups. (B) AP in each group. There was no difference in AP among OLD, RLD, and control groups. (C) TAPG in each group. Higher TAPG was seen in the RLD group than in the OLD and the control groups. (D) Adjusted TAPG in each group. Higher adjusted TAPG was seen in the RLD group than both the OLD and control groups. AP, intra-abdominal pressure; OLD, obstructive lung disease; RLD, restrictive lung disease; TAPG, thoraco-abdominal pressure gradient; TP, intra-thoracic pressure. Fig. 2 View largeDownload slide Underlying lung disease and thoracoabdominal pressure gradient. (A) TP in each group. More negative TP was seen in RLD group than both OLD and control groups. (B) AP in each group. There was no difference in AP among OLD, RLD, and control groups. (C) TAPG in each group. Higher TAPG was seen in the RLD group than in the OLD and the control groups. (D) Adjusted TAPG in each group. Higher adjusted TAPG was seen in the RLD group than both the OLD and control groups. AP, intra-abdominal pressure; OLD, obstructive lung disease; RLD, restrictive lung disease; TAPG, thoraco-abdominal pressure gradient; TP, intra-thoracic pressure. TP was more negative in patients diagnosed with RLD than in patients diagnosed with OLD (−7.5 vs. −0.6 mmHg, P < 0.001). Higher TAPG and higher adjusted TAPG were seen in the RLD group than in the OLD group (24.4 vs. 14.2 mmHg, P = 0.001; −1.7 vs. −11.5 mmHg, P = 0.003, respectively). TAPG and gastroesophageal reflux The correlation between TAPG and parameters of gastroesophageal reflux was assessed in all 77 pulmonary disease patients (Fig. 3). TAPG did not correlate with reflux parameters such as DeMeester score, total time pH < 4, and total number of reflux episodes. However, adjusted TAPG was positively correlated with each of these variables (DeMeester score: rs = 0.256, P = 0.024; total time pH < 4: rs = 0.259, P = 0.023; and total number of reflux episodes: rs = 0.268, P = 0.018, respectively). Fig. 3 View largeDownload slide Correlation between thoracoabdominal pressure gradient and each parameter for gastroesophageal reflux in patients with end-stage lung disease. (A) TAPG versus DeMeester score. There was no correlation between TAPG and DeMeester score. (B) TAPG versus total time of pH < 4. There was no correlation between TAPG and total time of pH < 4. (C) TAPG versus total number of reflux episodes. There was no correlation between TAPG and total number of reflux episodes. (D) Adjusted TAPG versus DeMeester score. There was a positive correlation between adjusted TAPG and DeMeester score. (E) Adjusted TAPG versus total time of pH < 4. There was a positive correlation between adjusted TAPG and total time of pH < 4. (F) Adjusted TAPG versus total number of reflux episodes. There was a positive correlation between adjusted TAPG and total number of reflux episodes. TAPG, thoracoabdominal pressure gradient. Fig. 3 View largeDownload slide Correlation between thoracoabdominal pressure gradient and each parameter for gastroesophageal reflux in patients with end-stage lung disease. (A) TAPG versus DeMeester score. There was no correlation between TAPG and DeMeester score. (B) TAPG versus total time of pH < 4. There was no correlation between TAPG and total time of pH < 4. (C) TAPG versus total number of reflux episodes. There was no correlation between TAPG and total number of reflux episodes. (D) Adjusted TAPG versus DeMeester score. There was a positive correlation between adjusted TAPG and DeMeester score. (E) Adjusted TAPG versus total time of pH < 4. There was a positive correlation between adjusted TAPG and total time of pH < 4. (F) Adjusted TAPG versus total number of reflux episodes. There was a positive correlation between adjusted TAPG and total number of reflux episodes. TAPG, thoracoabdominal pressure gradient. Adjusted TAPG > 0 mmHg was seen in 22/77 patients (28.6%). Figure 4 shows that patients with adjusted TAPG > 0 mmHg had significantly higher DeMeester scores, greater prevalence of pathological reflux, higher total time pH < 4, and more total number of reflux episodes compared with patients who had adjusted TAPG ≤ 0 mmHg (15.2 vs. 6.3, P = 0.006; 59.1 vs. 30.9%, P = 0.022; 4.5 vs. 1.5%, P = 0.003; 66.5 vs. 23.4, P = 0.012, respectively). Prevalence of esophageal dysmotility was similar between patients with adjusted TAPG > 0 mmHg and ≤ 0 mmHg (59.1% [13/22] vs. 58.2% [32/55], P = 0.942). Fig. 4 View largeDownload slide Thoracoabdominal pressure gradient and gastroesophageal reflux in patients with end-stage lung disease. (A) DeMeester score between patients with adjusted TAPG ≤ 0 and > 0 mmHg. Higher DeMeester score was seen in patients with adjusted TAPG > 0 mmHg. (B) Prevalence of pathological gastroesophageal reflux between patients with adjusted TAPG ≤ 0 and > 0 mmHg. Higher prevalence of pathological reflux (i.e., DeMeester score > 14.72) was seen in patients with adjusted TAPG > 0 mmHg. (C) Total time of pH < 4 between patients with adjusted TAPG ≤ 0 and > 0 mmHg. Longer time of pH < 4 was seen in patients with adjusted TAPG > 0 mmHg. (D) Total number of reflux episodes between patients with adjusted TAPG ≤ 0 and > 0 mmHg. A greater number of reflux episodes was seen in patients with adjusted TAPG > 0 mmHg. TAPG, thoracoabdominal pressure gradient. Fig. 4 View largeDownload slide Thoracoabdominal pressure gradient and gastroesophageal reflux in patients with end-stage lung disease. (A) DeMeester score between patients with adjusted TAPG ≤ 0 and > 0 mmHg. Higher DeMeester score was seen in patients with adjusted TAPG > 0 mmHg. (B) Prevalence of pathological gastroesophageal reflux between patients with adjusted TAPG ≤ 0 and > 0 mmHg. Higher prevalence of pathological reflux (i.e., DeMeester score > 14.72) was seen in patients with adjusted TAPG > 0 mmHg. (C) Total time of pH < 4 between patients with adjusted TAPG ≤ 0 and > 0 mmHg. Longer time of pH < 4 was seen in patients with adjusted TAPG > 0 mmHg. (D) Total number of reflux episodes between patients with adjusted TAPG ≤ 0 and > 0 mmHg. A greater number of reflux episodes was seen in patients with adjusted TAPG > 0 mmHg. TAPG, thoracoabdominal pressure gradient. Underlying lung disease and gastroesophageal reflux Parameters for gastroesophageal reflux were compared between patients diagnosed with OLD and patients diagnosed with RLD (Fig. 5). Patients in the RLD group had higher DeMeester scores, greater prevalence of pathological reflux, increased total % time of acid reflux, and more total number of reflux episodes compared with patients in the OLD group (14.5 vs. 5.8, P = 0.019; 47.6 vs. 24.2%, P = 0.038; 3.5 vs. 1.2%, P = 0.014; 53.4 vs. 22.5, P = 0.016, respectively). Fig. 5 View largeDownload slide Underlying lung disease and gastroesophageal reflux. (A) DeMeester score between OLD and RLD groups. Higher DeMeester score was seen in the RLD group. (B) Prevalence of pathological gastroesophageal reflux between the OLD and RLD groups. Higher prevalence of pathological reflux (i.e., DeMeester score > 14.72) was seen in the RLD group. (C) Total time of pH < 4 between the OLD and RLD groups. Longer time of pH < 4 was seen in the RLD group. (D) Total number of reflux episodes between the OLD and RLD groups. Greater number of reflux episodes was seen in the RLD group. OLD, obstructive lung disease; RLD, restrictive lung disease; TAPG, thoracoabdominal pressure gradient. Fig. 5 View largeDownload slide Underlying lung disease and gastroesophageal reflux. (A) DeMeester score between OLD and RLD groups. Higher DeMeester score was seen in the RLD group. (B) Prevalence of pathological gastroesophageal reflux between the OLD and RLD groups. Higher prevalence of pathological reflux (i.e., DeMeester score > 14.72) was seen in the RLD group. (C) Total time of pH < 4 between the OLD and RLD groups. Longer time of pH < 4 was seen in the RLD group. (D) Total number of reflux episodes between the OLD and RLD groups. Greater number of reflux episodes was seen in the RLD group. OLD, obstructive lung disease; RLD, restrictive lung disease; TAPG, thoracoabdominal pressure gradient. DISCUSSION GERD is common in patients diagnosed with advanced lung disease.1,2 Some researchers have proposed that more negative TP secondary to pulmonary disease results in greater TAPG, facilitating gastroesophageal reflux.3-6 Derangement of breathing mechanics due to underlying lung disease directly contributes to changes in intrathoracic pressures. Forced inspiration (as seen in patients diagnosed with RLD) can increase negative TP, ultimately increasing TAPG (Fig. 2). Increased TAPG plays an important role in the mechanism of gastroesophageal reflux, especially in obese patients or in those with severe pulmonary disease.3-6,8,9 The relationship between BMI and TAPG has been well studied in the literature. de Vries et al.8 and Derakhshan et al.9 have reported that obesity can increase AP, causing greater TAPG, and that BMI had positive correlation with reflux; however, they found no direct correlation between TAPG and gastroesophageal reflux. In this study, the majority of patients in the OLD group had advanced chronic obstructive pulmonary disease (COPD)—a disease that has been reported to decrease body weight.14 We showed that the patients in the OLD group had significantly lower BMI than patients in the RLD group or in the control group; however, it did not result in significant differences in AP across the 3 groups, even though BMI and AP were correlated in the total cohort (rs = 0.436, P < 0.001). This gap may suggest that the differences in BMI across the 3 groups are not directly responsible for the varied prevalence of pathological reflux among the groups. Therefore, in this study cohort, the derangement of TP due to underlying lung condition seems to be the primary factor for characterizing TAPG and also for the risk of GERD. Until now, few studies have investigated the association among underlying pulmonary disease, TAPG, and GERD. In 2004, Casanova et al.15 described 42 patients diagnosed with severe COPD, but found no correlation between transdiaphragmatic pressure gradient and GERD, even though pathological gastroesophageal reflux was highly prevalent in their cohort (62%). However, they did not adjust TAPG for LESP in their study. Basseri et al5 investigated TP in 30 lung transplant candidates in 2010, and reported that patients diagnosed with idiopathic pulmonary fibrosis (i.e., RLD) had more negative TP and greater DeMeester scores than patients diagnosed with COPD (i.e., OLD); however, they did not extend their study to assess the correlation between TAPG and GERD. GERD is a multifactorial disease. The competency of LES is widely accepted as the fundamental barrier mechanism against gastroesophageal reflux. Several parameters of LES on esophageal manometry have been established, described above (i.e., OL, AL, LESP, and LESPI).11,13 Table 1 shows that no statistically significant differences were observed in the LES parameters between the OLD and RLD groups. Although esophageal dysmotility can contribute to delayed acid clearance, exacerbating GERD,16 the prevalence of esophageal dysmotility was similar between the 2 groups (Table 1). Hiatal hernia has been also reported to be an independent risk factor for GERD;17 however, in this study, we excluded all patients with manometrically diagnosed hiatal hernia to remove it as a confounding factor. Previous authors have reported that even if the LES is manometrically normal, pathological reflux can be seen in 40% to 45% of patients undergoing pH testing.11,13 Ayazi et al.4 suggested that, even in a patient with a manometrically normal LES, gastroesophageal reflux may be induced if TAPG overcomes the pressure of the LES. Using conventional water-perfused manometry (8 channel pressure sensors), they reported that 85.2% of patients (23/27) with TAPG exceeding LESP had abnormal DeMeester scores. In this study, we modified this concept and set a new parameter—adjusted TAPG—which uses HRM and allows for accurate evaluation through 36 channel sensors placed at 1-cm intervals. We demonstrated that TAPG had no correlation per se with DeMeester score, total time pH < 4, or total number of reflux episodes in lung transplant candidates (Fig. 3A–C), which is in concordance with findings from previous studies;8,9,15 however, adjusted TAPG significantly correlated to all reflux parameters (Fig. 3D–F). This is consistent with findings of Ayazi et al.4 Our findings indicate that TAPG alone may not explain the impact of pressure gradient on GERD, but the TAPG adjusted by LESPap (i.e., LESP referenced to the pressure at the same level of AP measurement) is a novel predictor for pathological reflux. Figure 4 demonstrates that gastroesophageal reflux was significantly more common in patients who had TAPG greater than LESPap (i.e., adjusted TAPG > 0 mmHg). Increased TAPG was more common in patients with RLD than in patients with OLD or controls, indicating significantly more negative TP in the RLD group. This is likely due to the exaggerated inspiratory effort in patients diagnosed with RLD. Patients with RLD had a higher prevalence of pathological reflux compared with patients with OLD (Fig. 5), which is consistent with previously reported observations.5 This phenomenon could be due to higher TAPG and adjusted TAPG in the RLD cohort compared to those in the OLD cohort. This study is subject to certain limitations. Although it is a retrospective review of patient data, all data were collected prospectively and reanalyzed again according to the latest guidelines and in a blinded fashion. Hiatal hernia was diagnosed solely on the basis of HRM findings and although combined endoscopy and barium esophagogram may improve diagnostic accuracy, HRM still has a high sensitivity and specificity for hiatal hernia compared to endoscopy or barium esophagram alone.18 Symptomatic patients undergoing esophageal testing composed the control group, which may confound manometric and pH parameters. Further study, including analysis of patients with early-stage pulmonary disease and healthy controls may better clarify the roles of TAPG and adjusted TAPG in patients experiencing GERD. TAPG appears to be an important factor for efficacy of the LES barrier, especially in patients diagnosed with end-stage lung disease. In this study, higher adjusted TAPG increased the risk of pathological gastroesophageal reflux. Adjusted TAPG may provide further insights into the pathophysiology of GERD. Acknowledgment The authors are very grateful to Clare Prendergast for carefully proofreading the manuscript. References 1 D’Ovidio F , Singer L G , Hadjiliadis D et al. Prevalence of gastroesophageal reflux in end-stage lung disease candidates for lung transplant . Ann Thorac Surg 2005 ; 80 : 1254 – 60 . Google Scholar CrossRef Search ADS PubMed 2 Sweet M P , Herbella F A , Leard L et al. The prevalence of distal and proximal gastroesophageal reflux in patients awaiting lung transplantation . Ann Surg 2006 ; 244 : 491 – 7 . Google Scholar PubMed 3 Allaix M E , Fisichella P M , Noth I , Mendez B M , Patti M G . The pulmonary side of reflux disease: from heartburn to lung fibrosis . J Gastrointest Surg 2013 ; 17 : 1526 – 35 . Google Scholar CrossRef Search ADS PubMed 4 Ayazi S , DeMeester S R , Hsieh C C et al. Thoraco-abdominal pressure gradients during the phases of respiration contribute to gastroesophageal reflux disease . Dig Dis Sci 2011 ; 56 : 1718 – 22 . Google Scholar CrossRef Search ADS PubMed 5 Basseri B , Conklin J L , Pimentel M et al. Esophageal motor dysfunction and gastroesophageal reflux are prevalent in lung transplant candidates . Ann Thorac Surg 2010 ; 90 : 1630 – 6 . Google Scholar CrossRef Search ADS PubMed 6 Wood R K . Esophageal dysmotility, gastroesophageal reflux disease, and lung transplantation: what is the evidence? Curr Gastroenterol Rep 2015 ; 17 : 48 . Google Scholar CrossRef Search ADS PubMed 7 Ayazi S , Hagen J A , Chan L S et al. Obesity and gastroesophageal reflux: quantifying the association between body mass index, esophageal acid exposure, and lower esophageal sphincter status in a large series of patients with reflux symptoms . J Gastrointest Surg 2009 ; 13 : 1440 – 7 . Google Scholar CrossRef Search ADS PubMed 8 de Vries D R , van Herwaarden M A , Smout A J , Samsom M . Gastroesophageal pressure gradients in gastroesophageal reflux disease: relations with hiatal hernia, body mass index, and esophageal acid exposure . Am J Gastroenterol 2008 ; 103 : 1349 – 54 . Google Scholar CrossRef Search ADS PubMed 9 Derakhshan M H , Robertson E V , Fletcher J et al. Mechanism of association between BMI and dysfunction of the gastro-oesophageal barrier in patients with normal endoscopy . Gut 2012 ; 61 : 337 – 43 . Google Scholar CrossRef Search ADS PubMed 10 Kahrilas P J , Bredenoord A J , Fox M et al. The Chicago classification of esophageal motility disorders, v3.0 . Neurogastroenterol Motil 2015 ; 27 : 160 – 74 . Google Scholar CrossRef Search ADS PubMed 11 Zaninotto G , DeMeester T R , Schwizer W , Johansson K E , Cheng S C . The lower esophageal sphincter in health and disease . Am J Surg 1988 ; 155 : 104 – 11 . Google Scholar CrossRef Search ADS PubMed 12 Hoshino M , Sundaram A , Mittal S K . Role of the lower esophageal sphincter on acid exposure revisited with high-resolution manometry . J Am Coll Surg 2011 ; 213 : 743 – 50 . Google Scholar CrossRef Search ADS PubMed 13 Akimoto S , Singhal S , Masuda T , Mittal S K . Classification for esophagogastric junction (EGJ) complex based on physiology . Dis Esophagus 2017 ; 30 : 1 – 6 . Google Scholar CrossRef Search ADS 14 Rawal G , Yadav S . Nutrition in chronic obstructive pulmonary disease: a review . J Transl Int Med 2015 ; 3 : 151 – 4 . Google Scholar CrossRef Search ADS PubMed 15 Casanova C , Baudet J S , del Valle Velasco M et al. Increased gastro-oesophageal reflux disease in patients with severe COPD . Eur Respir J 2004 ; 23 : 841 – 5 . Google Scholar CrossRef Search ADS PubMed 16 Diener U , Patti M G , Molena D , Fisichella P M , Way L W . Esophageal dysmotility and gastroesophageal reflux disease . J Gastrointest Surg 2001 ; 5 : 260 – 5 . Google Scholar CrossRef Search ADS PubMed 17 van Hoeij F B , Smout A J , Bredenoord A J . Predictive value of routine esophageal high-resolution manometry for gastro-esophageal reflux disease . Neurogastroenterol Motil 2015 ; 27 : 963 – 70 . Google Scholar CrossRef Search ADS PubMed 18 Weijenborg P W , van Hoeij F B , Smout A J , Bredenoord A J . Accuracy of hiatal hernia detection with esophageal high-resolution manometry . Neurogastroenterol Motil 2015 ; 27 : 293 – 9 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diseases of the Esophagus Oxford University Press

Thoracoabdominal pressure gradient and gastroesophageal reflux: insights from lung transplant candidates

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Abstract

SUMMARY Advanced lung disease is associated with gastroesophageal reflux disease (GERD). The thoracoabdominal pressure gradient (TAPG) facilitates gastroesophageal reflux, but the effects of TAPG on gastroesophageal reflux in patients with pulmonary disease have not been well defined. Patients diagnosed with end-stage lung disease are expected to have the most extreme derangement in respiratory mechanics. The aim of this study is to explore the relationship between TAPG and reflux in lung transplant (LTx) candidates. We reviewed LTx recipients who underwent pretransplant esophageal high-resolution manometry and a 24-hour pH study. Patients were excluded if they were undergoing redo LTx, had manometric hiatal hernia, or had previously undergone foregut surgery. TAPG was defined as the intra-abdominal pressure minus the intrathoracic pressure during inspiration. Adjusted TAPG was calculated by the TAPG minus the resting lower esophageal sphincter (LES) pressure (LESP). Twenty-two patients with normal esophageal function tests (i.e., normal esophageal motility with neither manometric hiatal hernia nor pathological reflux on 24-hour pH monitoring) were selected as the pulmonary disease-free control group. In total, 204 patients underwent LTx between January 2015 and December 2016. Of these, 77 patients met inclusion criteria. We compared patients with obstructive lung disease (OLD, n = 33; 42.9%) and those with restrictive lung disease (RLD, n = 42; 54.5%). 2/77 patients (2.6%) had pulmonary arterial hypertension. GERD was more common in the RLD group than in the OLD group (24.2% vs. 47.6%, P = 0.038). TAPG was similar between the OLD group and the controls (14.2 vs. 15.3 mmHg, P = 0.850); however, patients in the RLD group had significantly higher TAPG than the controls (24.4 vs. 15.3 mmHg, P = 0.002). Although TAPG was not correlated with GERD, the adjusted TAPG correlated with reflux in all 77 patients with end-stage lung disease (DeMeester score, rs = 0.256, P = 0.024; total reflux time, rs = 0.259, P = 0.023; total number of reflux episodes, rs = 0.268, P = 0.018). Additionally, pathological reflux was seen in 59.1% of lung transplant candidates with adjusted TAPG greater than 0 mmHg (i.e., TAPG exceeding LESP); GERD was seen in 30.9% of patients who had an adjusted TAPG ≤ 0 mmHg. In summary, TAPG varies based on the underlying cause of lung disease. Higher adjusted TAPG increases pathological reflux, even if patients have normal antireflux anatomy and physiology (i.e., no hiatal hernia and manometrically normal LES function). Adjusted TAPG may provide further insights into the pathophysiology of GERD. INTRODUCTION Gastroesophageal reflux disease (GERD) has been associated with pulmonary disorders and is common in patients with advanced lung disease.1,2 However, the mechanism of the association between pulmonary disorder and gastroesophageal reflux remains to be elucidated. The stomach lies in a positive-pressure intra-abdominal position, while the esophagus is situated in the negative-pressure chest cavity. The pressure gradient between the abdominal and thoracic cavities is called the thoracoabdominal pressure gradient (TAPG). Because of the positive-pressure nature of the abdomen and the negative-pressure environment of the chest, there is a tendency for gastric fluid to flow from the stomach into the esophagus, and the TAPG determines the extent of this flow. The lower esophageal sphincter (LES) is the natural barrier against the retrograde flow of gastric juices. It has been suggested that physiologic changes in the thoracic cavity contribute to reflux because of increased TAPG across the LES.3-6 An elevated TAPG due to changes in pulmonary compliance or abdominal pressure is likely to further increase the magnitude of reflux. Increased body mass index (BMI) is known to result in greater intra-abdominal pressure; thus, individuals with above-average BMIs are more likely to experience GERD.7-9 However, few studies have focused on the role of intra-thoracic pressure as it relates to GERD. Patients diagnosed with end-stage lung disease are expected to have the most extreme derangement in respiratory mechanics, and these patients may help us understand how underlying lung disease is related to changes in TAPG. Furthermore, the respiratory mechanics of patients diagnosed with obstructive lung disease (OLD) (i.e., increased intrathoracic pressure during expiration), are opposite of those patients with a restrictive lung disease (RLD) (i.e., extreme negative pressure during inspiration). The aim of this study is to examine the association of GERD, TAPG, and underlying pulmonary disease in lung transplant candidates. MATERIALS AND METHODS Study population All patients who undergo lung transplant at our institution are prospectively entered into a database. We obtain complete foregut function testing on all patients whenever clinically possible. This includes high resolution manometry, 24-hour pH testing, endoscopy (performed by thoracic transplant surgeons) and gastric emptying studies. After Institutional Review Board approval (#PHXA-17-0172-71-18), we queried this database to identify patients who underwent pretransplant esophageal high-resolution manometry (HRM) and 24-hour pH study between January 2015 and December 2016. Esophageal HRM studies were reanalyzed using the Chicago Classification v 3.0.10 Underlying pulmonary disease was classified using United Network for Organ Sharing (UNOS) criteria: UNOS Criteria Group A, OLD; UNOS Criteria Group D, restrictive lung disease (RLD). We excluded patients who had undergone previous lung transplantation or foregut intervention, whose HRM or pH study was unavailable for reanalysis or was of poor quality, who had manometric hiatal hernia, or who were undergoing pH monitoring on acid suppression medications (proton pump inhibitors within 7 days or H2 receptor antagonists within 3 days before 24-hour pH study). We also established a control group comprising patients undergoing manometry and pH monitoring at our laboratory. Patients who had no history of pulmonary disease and healthy esophageal functional tests (i.e., normal esophageal motility without hiatal hernia on manometry, and nonpathological gastroesophageal reflux [DeMeester score ≤ 14.72] on 24-hour pH study) were used as control patients. From our database for esophageal functional testing, we identified patients who underwent both HRM and 24-hour pH study at our institution between January 2017 and December 2017. HRM studies were also reanalyzed using the Chicago Classification v 3.0.10 We excluded patients with known pulmonary lung disease, history of lung transplantation, history of foregut intervention, manometric hiatal hernia, any diagnosis of esophageal dysmotility (i.e., achalasia, esophagogastric junction [EGJ] outflow obstruction, diffuse esophageal spasm, jackhammer esophagus, absent contractility, ineffective esophageal motility, and fragmented peristalsis), poor-quality HRM or pH studies, pH monitoring with acid suppression medications, and abnormal DeMeester score (>14.72). High-resolution manometry HRM was performed with a 36-channel probe with circumferential sensors at 1-cm intervals (Sierra Scientific Instruments Inc., Los Angeles, CA). These studies were reanalyzed by a single author (TM) using Manoview software (Sierra Scientific Instruments Inc.). This author was blinded to patients’ 24-hour pH monitoring results. The esophageal pressure topography of ten 5-mL water swallows was diagnosed according to the Chicago Classification v 3.0.10 We also assessed EGJ barrier function against gastroesophageal reflux, using variables that have been previously established; namely, overall LES length (OL), abdominal LES length (AL), resting LES pressure (LESP),11 and LESP integral (LESPI).12 Thoracoabdominal pressure gradient Using the resting phase of the HRM studies, intra-abdominal pressure (AP), intrathoracic pressure (TP), and TAPG were assessed. AP was defined as the pressure 1 cm below the lower border of the crus at inspiration (referenced to atmospheric pressure). TP was defined as the pressure 5 cm above the upper border of the LES at inspiration (referenced to atmospheric pressure). This position is also the location of placement of a pH sensor for ambulatory pH monitoring. TAPG was calculated as AP minus TP (Fig. 1A). Fig. 1 View largeDownload slide Thoracoabdominal pressure gradient. (A) TAPG. (B) Adjusted TAPG. AP, intra-abdominal pressure; CD, crural diaphragm; E, expiration; I, inspiration; LES, lower esophageal sphincter; LESPap; LES pressure referred to AP; TAPG, thoracoabdominal pressure gradient; TP, intrathoracic pressure. Fig. 1 View largeDownload slide Thoracoabdominal pressure gradient. (A) TAPG. (B) Adjusted TAPG. AP, intra-abdominal pressure; CD, crural diaphragm; E, expiration; I, inspiration; LES, lower esophageal sphincter; LESPap; LES pressure referred to AP; TAPG, thoracoabdominal pressure gradient; TP, intrathoracic pressure. LES pressure (LESPap), referenced to the pressure at the same level of AP measurement (i.e., 1 cm below the lower border of the crus) was also assessed, and adjusted TAPG was calculated as TAPG minus LESPap (Fig. 1B). The cutoff value of adjusted TAPG to predict the risk of pathological reflux was set at >0 mmHg, according to a hypothesis previously suggested by Ayazi et al.4 Briefly, they described that gastroesophageal reflux may be induced if TAPG overcomes LESP, which works as a fundamental antireflux pressure. 24-hour pH monitoring Ambulatory esophageal pH monitoring was performed using either a catheter-based system (Digitrapper 400pH®; Medtronic, Minneapolis, MN) or a capsule-based system (Bravo®; Medtronic, Minneapolis, MN), according to previously described methods.13 Briefly, the catheter-based pH probe was passed transnasally and positioned 5 cm above the upper border of the LES (defined on manometry), while the capsule was passed transorally and positioned 6 cm above the gastroesophageal junction under endoscopic guidance. For the capsule-based system, the DeMeester score was calculated as the mean of the scores over 2 days. Statistical analysis All statistical analyses were performed using the SPSS version 22.0.0.0 (Armonk, NY). Chi-square test or Fisher exact test were used to compare categorical variables. The Mann-Whitney U test was used to compare continuous variables. Spearman's correlation was used to test the association between two ranked variables. Continuous variables were expressed as median and interquartile range. Statistical significance was set at P < 0.05. RESULTS In total, 204 patients underwent lung transplant during the study period. Of these, 174 patients underwent preoperative HRM. Patients with prior lung transplantation (n = 13), history of previous foregut intervention (n = 12), HRM unavailable for reanalysis or of poor quality (n = 33), manometric hiatal hernia (n = 34), and unavailable pH study (n = 5) were excluded. Not all patients had a complete workup as some were evaluated urgently or were too ill to undergo complete testing. The remaining 77 patients who met the study criteria made up the pulmonary disease group. Thirty-three patients had OLD, 42 patients had RLD, and 2 were diagnosed with pulmonary arterial hypertension. Abnormal DeMeester score (>14.72) was seen in 30/77 (39.0%) patients. The control group was composed of 22 patients who had no history of pulmonary disease, normal esophageal motility without manometric hiatal hernia, and nonpathological gastroesophageal reflux (i.e., DeMeester score ≤ 14.72) on 24-hour pH study. The demographics of the entire study population are summarized in Table 1. Age and sex were similar between patients with OLD and RLD. Patients in the pulmonary disease group were older than patients in the control group (64 vs. 52 years, P < 0.001). Table 1 Patient characteristics Variable All pulmonary disease OLD RLD Control n = 77 n = 33 n = 42 n = 22 Age, years 64.0 (57.0–68.0)*** 62.0 (57.0–68.0)** 65.5 (60.0–69.0)*** 52.0 (42.0–64.0) Sex, male:female† 44:33* 15:18 29:13** 6:16 BMI, kg/m2† 26.0 (22.9–29.6)** 24.0 (21.0–27.3)** 27.3 (24.3–30.6) 30.4 (25.1–38.7) DeMeester score 9.3 (2.9–21.5) 5.8 (1.8–14.7) 14.5 (4.0–28.0)** 4.9 (3.4–10.1) Abnormal DeMeester score (>14.72) 30 (39.0%)*** 8 (24.2%)* 20 (47.6%)*** 0 LES function LESP, mmHg 33.8 (24.4–40.6) 33.6 (23.3–41.5) 34.1 (26.8–40.0) 30.4 (25.1–38.7) Hypotensive LESP (<13 mmHg) 2 (2.6%) 1 (3.0%) 1 (2.4%) 0 LESPI, mmHg·s·cm 269.1 (151.0–467.3) 277.5 (111.6–744.7) 281.6 (178.0–360.5) 325.6 (55.8–480.1) OL, cm 2.9 (2.4–3.5) 2.7 (2.4–3.5) 3.0 (2.6–3.5) 3.1 (2.7–3.6) AL, cm 2.4 (2.1–2.8) 2.4 (2.1–2.8) 2.5 (2.1–2.9) 2.8 (2.3–3.2) HRM diagnosis Normal esophageal motility 32 (41.6%)*** 18 (54.5%)*** 14 (33.3%)*** 22 (100.0%) Esophageal dysmotility 45 (58.4%)*** 15 (45.5%)*** 28 (66.7%)*** 0 IEM 25 (32.5%) 8 (24.2%) 16 (38.1%) – Absent contractility† 7 (9.1%) 0 6 (14.3%) – Fragmented peristalsis 3 (3.9%) 1 (3.0%) 2 (4.8%) – EGJ outflow obstruction 8 (10.4%) 5 (15.2%) 3 (7.1%) – Achalasia 2 (2.6%) 1 (3.0%) 1 (2.4%) – Variable All pulmonary disease OLD RLD Control n = 77 n = 33 n = 42 n = 22 Age, years 64.0 (57.0–68.0)*** 62.0 (57.0–68.0)** 65.5 (60.0–69.0)*** 52.0 (42.0–64.0) Sex, male:female† 44:33* 15:18 29:13** 6:16 BMI, kg/m2† 26.0 (22.9–29.6)** 24.0 (21.0–27.3)** 27.3 (24.3–30.6) 30.4 (25.1–38.7) DeMeester score 9.3 (2.9–21.5) 5.8 (1.8–14.7) 14.5 (4.0–28.0)** 4.9 (3.4–10.1) Abnormal DeMeester score (>14.72) 30 (39.0%)*** 8 (24.2%)* 20 (47.6%)*** 0 LES function LESP, mmHg 33.8 (24.4–40.6) 33.6 (23.3–41.5) 34.1 (26.8–40.0) 30.4 (25.1–38.7) Hypotensive LESP (<13 mmHg) 2 (2.6%) 1 (3.0%) 1 (2.4%) 0 LESPI, mmHg·s·cm 269.1 (151.0–467.3) 277.5 (111.6–744.7) 281.6 (178.0–360.5) 325.6 (55.8–480.1) OL, cm 2.9 (2.4–3.5) 2.7 (2.4–3.5) 3.0 (2.6–3.5) 3.1 (2.7–3.6) AL, cm 2.4 (2.1–2.8) 2.4 (2.1–2.8) 2.5 (2.1–2.9) 2.8 (2.3–3.2) HRM diagnosis Normal esophageal motility 32 (41.6%)*** 18 (54.5%)*** 14 (33.3%)*** 22 (100.0%) Esophageal dysmotility 45 (58.4%)*** 15 (45.5%)*** 28 (66.7%)*** 0 IEM 25 (32.5%) 8 (24.2%) 16 (38.1%) – Absent contractility† 7 (9.1%) 0 6 (14.3%) – Fragmented peristalsis 3 (3.9%) 1 (3.0%) 2 (4.8%) – EGJ outflow obstruction 8 (10.4%) 5 (15.2%) 3 (7.1%) – Achalasia 2 (2.6%) 1 (3.0%) 1 (2.4%) – Continuous variables were expressed as the median (IQR)$$\|$$ Categorical variables were expressed as number (%). *P < 0.05, **P < 0.01, ***P < 0.001 compared with control group. †P < 0.05 compared between OLD and RLD. AL, abdominal LES length; BMI, body mass index; EGJ, esophagogastric junction, HRM, high-resolution manometry; IEM, ineffective esophageal motility; LES, lower esophageal sphincter; LESP, resting LES pressure; LESPI, LES pressure integral; OL, overall LES length; OLD, obstructive lung disease; RLD, restrictive lung disease. View Large Table 1 Patient characteristics Variable All pulmonary disease OLD RLD Control n = 77 n = 33 n = 42 n = 22 Age, years 64.0 (57.0–68.0)*** 62.0 (57.0–68.0)** 65.5 (60.0–69.0)*** 52.0 (42.0–64.0) Sex, male:female† 44:33* 15:18 29:13** 6:16 BMI, kg/m2† 26.0 (22.9–29.6)** 24.0 (21.0–27.3)** 27.3 (24.3–30.6) 30.4 (25.1–38.7) DeMeester score 9.3 (2.9–21.5) 5.8 (1.8–14.7) 14.5 (4.0–28.0)** 4.9 (3.4–10.1) Abnormal DeMeester score (>14.72) 30 (39.0%)*** 8 (24.2%)* 20 (47.6%)*** 0 LES function LESP, mmHg 33.8 (24.4–40.6) 33.6 (23.3–41.5) 34.1 (26.8–40.0) 30.4 (25.1–38.7) Hypotensive LESP (<13 mmHg) 2 (2.6%) 1 (3.0%) 1 (2.4%) 0 LESPI, mmHg·s·cm 269.1 (151.0–467.3) 277.5 (111.6–744.7) 281.6 (178.0–360.5) 325.6 (55.8–480.1) OL, cm 2.9 (2.4–3.5) 2.7 (2.4–3.5) 3.0 (2.6–3.5) 3.1 (2.7–3.6) AL, cm 2.4 (2.1–2.8) 2.4 (2.1–2.8) 2.5 (2.1–2.9) 2.8 (2.3–3.2) HRM diagnosis Normal esophageal motility 32 (41.6%)*** 18 (54.5%)*** 14 (33.3%)*** 22 (100.0%) Esophageal dysmotility 45 (58.4%)*** 15 (45.5%)*** 28 (66.7%)*** 0 IEM 25 (32.5%) 8 (24.2%) 16 (38.1%) – Absent contractility† 7 (9.1%) 0 6 (14.3%) – Fragmented peristalsis 3 (3.9%) 1 (3.0%) 2 (4.8%) – EGJ outflow obstruction 8 (10.4%) 5 (15.2%) 3 (7.1%) – Achalasia 2 (2.6%) 1 (3.0%) 1 (2.4%) – Variable All pulmonary disease OLD RLD Control n = 77 n = 33 n = 42 n = 22 Age, years 64.0 (57.0–68.0)*** 62.0 (57.0–68.0)** 65.5 (60.0–69.0)*** 52.0 (42.0–64.0) Sex, male:female† 44:33* 15:18 29:13** 6:16 BMI, kg/m2† 26.0 (22.9–29.6)** 24.0 (21.0–27.3)** 27.3 (24.3–30.6) 30.4 (25.1–38.7) DeMeester score 9.3 (2.9–21.5) 5.8 (1.8–14.7) 14.5 (4.0–28.0)** 4.9 (3.4–10.1) Abnormal DeMeester score (>14.72) 30 (39.0%)*** 8 (24.2%)* 20 (47.6%)*** 0 LES function LESP, mmHg 33.8 (24.4–40.6) 33.6 (23.3–41.5) 34.1 (26.8–40.0) 30.4 (25.1–38.7) Hypotensive LESP (<13 mmHg) 2 (2.6%) 1 (3.0%) 1 (2.4%) 0 LESPI, mmHg·s·cm 269.1 (151.0–467.3) 277.5 (111.6–744.7) 281.6 (178.0–360.5) 325.6 (55.8–480.1) OL, cm 2.9 (2.4–3.5) 2.7 (2.4–3.5) 3.0 (2.6–3.5) 3.1 (2.7–3.6) AL, cm 2.4 (2.1–2.8) 2.4 (2.1–2.8) 2.5 (2.1–2.9) 2.8 (2.3–3.2) HRM diagnosis Normal esophageal motility 32 (41.6%)*** 18 (54.5%)*** 14 (33.3%)*** 22 (100.0%) Esophageal dysmotility 45 (58.4%)*** 15 (45.5%)*** 28 (66.7%)*** 0 IEM 25 (32.5%) 8 (24.2%) 16 (38.1%) – Absent contractility† 7 (9.1%) 0 6 (14.3%) – Fragmented peristalsis 3 (3.9%) 1 (3.0%) 2 (4.8%) – EGJ outflow obstruction 8 (10.4%) 5 (15.2%) 3 (7.1%) – Achalasia 2 (2.6%) 1 (3.0%) 1 (2.4%) – Continuous variables were expressed as the median (IQR)$$\|$$ Categorical variables were expressed as number (%). *P < 0.05, **P < 0.01, ***P < 0.001 compared with control group. †P < 0.05 compared between OLD and RLD. AL, abdominal LES length; BMI, body mass index; EGJ, esophagogastric junction, HRM, high-resolution manometry; IEM, ineffective esophageal motility; LES, lower esophageal sphincter; LESP, resting LES pressure; LESPI, LES pressure integral; OL, overall LES length; OLD, obstructive lung disease; RLD, restrictive lung disease. View Large BMI was similar between RLD and control patients (27.3 vs 30.4 kg/m2, P = 0.070); however, patients in the OLD cohort had significantly lower BMI (24.0 kg/m2) than patients in the RLD and control groups (P = 0.010 and P = 0.001, respectively). HRM parameters for LES function and prevalence of esophageal dysmotility were similar between OLD and RLD groups. Underlying lung disease and TAPG Figure 2 depicts the differences in TP, AP, TAPG, and adjusted TAPG among the 3 groups. No difference in AP was observed across the 3 groups, although there was positive correlation between AP and BMI in the total cohort (rs = 0.436, P < 0.001). TP, TAPG, and adjusted TAPG did not differ between the OLD and control groups. TP in RLD group was more negative than in the control group (−7.5 vs. −0.7 mmHg, P = 0.002), and patients in the RLD group had greater TAPG and adjusted TAPG compared with patients in the control group (24.4 vs. 15.3 mmHg, P = 0.002; −1.7 vs. −9.5 mmHg, P = 0.043, respectively). Fig. 2 View largeDownload slide Underlying lung disease and thoracoabdominal pressure gradient. (A) TP in each group. More negative TP was seen in RLD group than both OLD and control groups. (B) AP in each group. There was no difference in AP among OLD, RLD, and control groups. (C) TAPG in each group. Higher TAPG was seen in the RLD group than in the OLD and the control groups. (D) Adjusted TAPG in each group. Higher adjusted TAPG was seen in the RLD group than both the OLD and control groups. AP, intra-abdominal pressure; OLD, obstructive lung disease; RLD, restrictive lung disease; TAPG, thoraco-abdominal pressure gradient; TP, intra-thoracic pressure. Fig. 2 View largeDownload slide Underlying lung disease and thoracoabdominal pressure gradient. (A) TP in each group. More negative TP was seen in RLD group than both OLD and control groups. (B) AP in each group. There was no difference in AP among OLD, RLD, and control groups. (C) TAPG in each group. Higher TAPG was seen in the RLD group than in the OLD and the control groups. (D) Adjusted TAPG in each group. Higher adjusted TAPG was seen in the RLD group than both the OLD and control groups. AP, intra-abdominal pressure; OLD, obstructive lung disease; RLD, restrictive lung disease; TAPG, thoraco-abdominal pressure gradient; TP, intra-thoracic pressure. TP was more negative in patients diagnosed with RLD than in patients diagnosed with OLD (−7.5 vs. −0.6 mmHg, P < 0.001). Higher TAPG and higher adjusted TAPG were seen in the RLD group than in the OLD group (24.4 vs. 14.2 mmHg, P = 0.001; −1.7 vs. −11.5 mmHg, P = 0.003, respectively). TAPG and gastroesophageal reflux The correlation between TAPG and parameters of gastroesophageal reflux was assessed in all 77 pulmonary disease patients (Fig. 3). TAPG did not correlate with reflux parameters such as DeMeester score, total time pH < 4, and total number of reflux episodes. However, adjusted TAPG was positively correlated with each of these variables (DeMeester score: rs = 0.256, P = 0.024; total time pH < 4: rs = 0.259, P = 0.023; and total number of reflux episodes: rs = 0.268, P = 0.018, respectively). Fig. 3 View largeDownload slide Correlation between thoracoabdominal pressure gradient and each parameter for gastroesophageal reflux in patients with end-stage lung disease. (A) TAPG versus DeMeester score. There was no correlation between TAPG and DeMeester score. (B) TAPG versus total time of pH < 4. There was no correlation between TAPG and total time of pH < 4. (C) TAPG versus total number of reflux episodes. There was no correlation between TAPG and total number of reflux episodes. (D) Adjusted TAPG versus DeMeester score. There was a positive correlation between adjusted TAPG and DeMeester score. (E) Adjusted TAPG versus total time of pH < 4. There was a positive correlation between adjusted TAPG and total time of pH < 4. (F) Adjusted TAPG versus total number of reflux episodes. There was a positive correlation between adjusted TAPG and total number of reflux episodes. TAPG, thoracoabdominal pressure gradient. Fig. 3 View largeDownload slide Correlation between thoracoabdominal pressure gradient and each parameter for gastroesophageal reflux in patients with end-stage lung disease. (A) TAPG versus DeMeester score. There was no correlation between TAPG and DeMeester score. (B) TAPG versus total time of pH < 4. There was no correlation between TAPG and total time of pH < 4. (C) TAPG versus total number of reflux episodes. There was no correlation between TAPG and total number of reflux episodes. (D) Adjusted TAPG versus DeMeester score. There was a positive correlation between adjusted TAPG and DeMeester score. (E) Adjusted TAPG versus total time of pH < 4. There was a positive correlation between adjusted TAPG and total time of pH < 4. (F) Adjusted TAPG versus total number of reflux episodes. There was a positive correlation between adjusted TAPG and total number of reflux episodes. TAPG, thoracoabdominal pressure gradient. Adjusted TAPG > 0 mmHg was seen in 22/77 patients (28.6%). Figure 4 shows that patients with adjusted TAPG > 0 mmHg had significantly higher DeMeester scores, greater prevalence of pathological reflux, higher total time pH < 4, and more total number of reflux episodes compared with patients who had adjusted TAPG ≤ 0 mmHg (15.2 vs. 6.3, P = 0.006; 59.1 vs. 30.9%, P = 0.022; 4.5 vs. 1.5%, P = 0.003; 66.5 vs. 23.4, P = 0.012, respectively). Prevalence of esophageal dysmotility was similar between patients with adjusted TAPG > 0 mmHg and ≤ 0 mmHg (59.1% [13/22] vs. 58.2% [32/55], P = 0.942). Fig. 4 View largeDownload slide Thoracoabdominal pressure gradient and gastroesophageal reflux in patients with end-stage lung disease. (A) DeMeester score between patients with adjusted TAPG ≤ 0 and > 0 mmHg. Higher DeMeester score was seen in patients with adjusted TAPG > 0 mmHg. (B) Prevalence of pathological gastroesophageal reflux between patients with adjusted TAPG ≤ 0 and > 0 mmHg. Higher prevalence of pathological reflux (i.e., DeMeester score > 14.72) was seen in patients with adjusted TAPG > 0 mmHg. (C) Total time of pH < 4 between patients with adjusted TAPG ≤ 0 and > 0 mmHg. Longer time of pH < 4 was seen in patients with adjusted TAPG > 0 mmHg. (D) Total number of reflux episodes between patients with adjusted TAPG ≤ 0 and > 0 mmHg. A greater number of reflux episodes was seen in patients with adjusted TAPG > 0 mmHg. TAPG, thoracoabdominal pressure gradient. Fig. 4 View largeDownload slide Thoracoabdominal pressure gradient and gastroesophageal reflux in patients with end-stage lung disease. (A) DeMeester score between patients with adjusted TAPG ≤ 0 and > 0 mmHg. Higher DeMeester score was seen in patients with adjusted TAPG > 0 mmHg. (B) Prevalence of pathological gastroesophageal reflux between patients with adjusted TAPG ≤ 0 and > 0 mmHg. Higher prevalence of pathological reflux (i.e., DeMeester score > 14.72) was seen in patients with adjusted TAPG > 0 mmHg. (C) Total time of pH < 4 between patients with adjusted TAPG ≤ 0 and > 0 mmHg. Longer time of pH < 4 was seen in patients with adjusted TAPG > 0 mmHg. (D) Total number of reflux episodes between patients with adjusted TAPG ≤ 0 and > 0 mmHg. A greater number of reflux episodes was seen in patients with adjusted TAPG > 0 mmHg. TAPG, thoracoabdominal pressure gradient. Underlying lung disease and gastroesophageal reflux Parameters for gastroesophageal reflux were compared between patients diagnosed with OLD and patients diagnosed with RLD (Fig. 5). Patients in the RLD group had higher DeMeester scores, greater prevalence of pathological reflux, increased total % time of acid reflux, and more total number of reflux episodes compared with patients in the OLD group (14.5 vs. 5.8, P = 0.019; 47.6 vs. 24.2%, P = 0.038; 3.5 vs. 1.2%, P = 0.014; 53.4 vs. 22.5, P = 0.016, respectively). Fig. 5 View largeDownload slide Underlying lung disease and gastroesophageal reflux. (A) DeMeester score between OLD and RLD groups. Higher DeMeester score was seen in the RLD group. (B) Prevalence of pathological gastroesophageal reflux between the OLD and RLD groups. Higher prevalence of pathological reflux (i.e., DeMeester score > 14.72) was seen in the RLD group. (C) Total time of pH < 4 between the OLD and RLD groups. Longer time of pH < 4 was seen in the RLD group. (D) Total number of reflux episodes between the OLD and RLD groups. Greater number of reflux episodes was seen in the RLD group. OLD, obstructive lung disease; RLD, restrictive lung disease; TAPG, thoracoabdominal pressure gradient. Fig. 5 View largeDownload slide Underlying lung disease and gastroesophageal reflux. (A) DeMeester score between OLD and RLD groups. Higher DeMeester score was seen in the RLD group. (B) Prevalence of pathological gastroesophageal reflux between the OLD and RLD groups. Higher prevalence of pathological reflux (i.e., DeMeester score > 14.72) was seen in the RLD group. (C) Total time of pH < 4 between the OLD and RLD groups. Longer time of pH < 4 was seen in the RLD group. (D) Total number of reflux episodes between the OLD and RLD groups. Greater number of reflux episodes was seen in the RLD group. OLD, obstructive lung disease; RLD, restrictive lung disease; TAPG, thoracoabdominal pressure gradient. DISCUSSION GERD is common in patients diagnosed with advanced lung disease.1,2 Some researchers have proposed that more negative TP secondary to pulmonary disease results in greater TAPG, facilitating gastroesophageal reflux.3-6 Derangement of breathing mechanics due to underlying lung disease directly contributes to changes in intrathoracic pressures. Forced inspiration (as seen in patients diagnosed with RLD) can increase negative TP, ultimately increasing TAPG (Fig. 2). Increased TAPG plays an important role in the mechanism of gastroesophageal reflux, especially in obese patients or in those with severe pulmonary disease.3-6,8,9 The relationship between BMI and TAPG has been well studied in the literature. de Vries et al.8 and Derakhshan et al.9 have reported that obesity can increase AP, causing greater TAPG, and that BMI had positive correlation with reflux; however, they found no direct correlation between TAPG and gastroesophageal reflux. In this study, the majority of patients in the OLD group had advanced chronic obstructive pulmonary disease (COPD)—a disease that has been reported to decrease body weight.14 We showed that the patients in the OLD group had significantly lower BMI than patients in the RLD group or in the control group; however, it did not result in significant differences in AP across the 3 groups, even though BMI and AP were correlated in the total cohort (rs = 0.436, P < 0.001). This gap may suggest that the differences in BMI across the 3 groups are not directly responsible for the varied prevalence of pathological reflux among the groups. Therefore, in this study cohort, the derangement of TP due to underlying lung condition seems to be the primary factor for characterizing TAPG and also for the risk of GERD. Until now, few studies have investigated the association among underlying pulmonary disease, TAPG, and GERD. In 2004, Casanova et al.15 described 42 patients diagnosed with severe COPD, but found no correlation between transdiaphragmatic pressure gradient and GERD, even though pathological gastroesophageal reflux was highly prevalent in their cohort (62%). However, they did not adjust TAPG for LESP in their study. Basseri et al5 investigated TP in 30 lung transplant candidates in 2010, and reported that patients diagnosed with idiopathic pulmonary fibrosis (i.e., RLD) had more negative TP and greater DeMeester scores than patients diagnosed with COPD (i.e., OLD); however, they did not extend their study to assess the correlation between TAPG and GERD. GERD is a multifactorial disease. The competency of LES is widely accepted as the fundamental barrier mechanism against gastroesophageal reflux. Several parameters of LES on esophageal manometry have been established, described above (i.e., OL, AL, LESP, and LESPI).11,13 Table 1 shows that no statistically significant differences were observed in the LES parameters between the OLD and RLD groups. Although esophageal dysmotility can contribute to delayed acid clearance, exacerbating GERD,16 the prevalence of esophageal dysmotility was similar between the 2 groups (Table 1). Hiatal hernia has been also reported to be an independent risk factor for GERD;17 however, in this study, we excluded all patients with manometrically diagnosed hiatal hernia to remove it as a confounding factor. Previous authors have reported that even if the LES is manometrically normal, pathological reflux can be seen in 40% to 45% of patients undergoing pH testing.11,13 Ayazi et al.4 suggested that, even in a patient with a manometrically normal LES, gastroesophageal reflux may be induced if TAPG overcomes the pressure of the LES. Using conventional water-perfused manometry (8 channel pressure sensors), they reported that 85.2% of patients (23/27) with TAPG exceeding LESP had abnormal DeMeester scores. In this study, we modified this concept and set a new parameter—adjusted TAPG—which uses HRM and allows for accurate evaluation through 36 channel sensors placed at 1-cm intervals. We demonstrated that TAPG had no correlation per se with DeMeester score, total time pH < 4, or total number of reflux episodes in lung transplant candidates (Fig. 3A–C), which is in concordance with findings from previous studies;8,9,15 however, adjusted TAPG significantly correlated to all reflux parameters (Fig. 3D–F). This is consistent with findings of Ayazi et al.4 Our findings indicate that TAPG alone may not explain the impact of pressure gradient on GERD, but the TAPG adjusted by LESPap (i.e., LESP referenced to the pressure at the same level of AP measurement) is a novel predictor for pathological reflux. Figure 4 demonstrates that gastroesophageal reflux was significantly more common in patients who had TAPG greater than LESPap (i.e., adjusted TAPG > 0 mmHg). Increased TAPG was more common in patients with RLD than in patients with OLD or controls, indicating significantly more negative TP in the RLD group. This is likely due to the exaggerated inspiratory effort in patients diagnosed with RLD. Patients with RLD had a higher prevalence of pathological reflux compared with patients with OLD (Fig. 5), which is consistent with previously reported observations.5 This phenomenon could be due to higher TAPG and adjusted TAPG in the RLD cohort compared to those in the OLD cohort. This study is subject to certain limitations. Although it is a retrospective review of patient data, all data were collected prospectively and reanalyzed again according to the latest guidelines and in a blinded fashion. Hiatal hernia was diagnosed solely on the basis of HRM findings and although combined endoscopy and barium esophagogram may improve diagnostic accuracy, HRM still has a high sensitivity and specificity for hiatal hernia compared to endoscopy or barium esophagram alone.18 Symptomatic patients undergoing esophageal testing composed the control group, which may confound manometric and pH parameters. Further study, including analysis of patients with early-stage pulmonary disease and healthy controls may better clarify the roles of TAPG and adjusted TAPG in patients experiencing GERD. TAPG appears to be an important factor for efficacy of the LES barrier, especially in patients diagnosed with end-stage lung disease. In this study, higher adjusted TAPG increased the risk of pathological gastroesophageal reflux. Adjusted TAPG may provide further insights into the pathophysiology of GERD. Acknowledgment The authors are very grateful to Clare Prendergast for carefully proofreading the manuscript. References 1 D’Ovidio F , Singer L G , Hadjiliadis D et al. Prevalence of gastroesophageal reflux in end-stage lung disease candidates for lung transplant . Ann Thorac Surg 2005 ; 80 : 1254 – 60 . Google Scholar CrossRef Search ADS PubMed 2 Sweet M P , Herbella F A , Leard L et al. The prevalence of distal and proximal gastroesophageal reflux in patients awaiting lung transplantation . Ann Surg 2006 ; 244 : 491 – 7 . Google Scholar PubMed 3 Allaix M E , Fisichella P M , Noth I , Mendez B M , Patti M G . The pulmonary side of reflux disease: from heartburn to lung fibrosis . J Gastrointest Surg 2013 ; 17 : 1526 – 35 . Google Scholar CrossRef Search ADS PubMed 4 Ayazi S , DeMeester S R , Hsieh C C et al. Thoraco-abdominal pressure gradients during the phases of respiration contribute to gastroesophageal reflux disease . Dig Dis Sci 2011 ; 56 : 1718 – 22 . Google Scholar CrossRef Search ADS PubMed 5 Basseri B , Conklin J L , Pimentel M et al. Esophageal motor dysfunction and gastroesophageal reflux are prevalent in lung transplant candidates . Ann Thorac Surg 2010 ; 90 : 1630 – 6 . Google Scholar CrossRef Search ADS PubMed 6 Wood R K . Esophageal dysmotility, gastroesophageal reflux disease, and lung transplantation: what is the evidence? Curr Gastroenterol Rep 2015 ; 17 : 48 . Google Scholar CrossRef Search ADS PubMed 7 Ayazi S , Hagen J A , Chan L S et al. Obesity and gastroesophageal reflux: quantifying the association between body mass index, esophageal acid exposure, and lower esophageal sphincter status in a large series of patients with reflux symptoms . J Gastrointest Surg 2009 ; 13 : 1440 – 7 . Google Scholar CrossRef Search ADS PubMed 8 de Vries D R , van Herwaarden M A , Smout A J , Samsom M . Gastroesophageal pressure gradients in gastroesophageal reflux disease: relations with hiatal hernia, body mass index, and esophageal acid exposure . Am J Gastroenterol 2008 ; 103 : 1349 – 54 . Google Scholar CrossRef Search ADS PubMed 9 Derakhshan M H , Robertson E V , Fletcher J et al. Mechanism of association between BMI and dysfunction of the gastro-oesophageal barrier in patients with normal endoscopy . Gut 2012 ; 61 : 337 – 43 . Google Scholar CrossRef Search ADS PubMed 10 Kahrilas P J , Bredenoord A J , Fox M et al. The Chicago classification of esophageal motility disorders, v3.0 . Neurogastroenterol Motil 2015 ; 27 : 160 – 74 . Google Scholar CrossRef Search ADS PubMed 11 Zaninotto G , DeMeester T R , Schwizer W , Johansson K E , Cheng S C . The lower esophageal sphincter in health and disease . Am J Surg 1988 ; 155 : 104 – 11 . Google Scholar CrossRef Search ADS PubMed 12 Hoshino M , Sundaram A , Mittal S K . Role of the lower esophageal sphincter on acid exposure revisited with high-resolution manometry . J Am Coll Surg 2011 ; 213 : 743 – 50 . Google Scholar CrossRef Search ADS PubMed 13 Akimoto S , Singhal S , Masuda T , Mittal S K . Classification for esophagogastric junction (EGJ) complex based on physiology . Dis Esophagus 2017 ; 30 : 1 – 6 . Google Scholar CrossRef Search ADS 14 Rawal G , Yadav S . Nutrition in chronic obstructive pulmonary disease: a review . J Transl Int Med 2015 ; 3 : 151 – 4 . Google Scholar CrossRef Search ADS PubMed 15 Casanova C , Baudet J S , del Valle Velasco M et al. Increased gastro-oesophageal reflux disease in patients with severe COPD . Eur Respir J 2004 ; 23 : 841 – 5 . Google Scholar CrossRef Search ADS PubMed 16 Diener U , Patti M G , Molena D , Fisichella P M , Way L W . Esophageal dysmotility and gastroesophageal reflux disease . J Gastrointest Surg 2001 ; 5 : 260 – 5 . Google Scholar CrossRef Search ADS PubMed 17 van Hoeij F B , Smout A J , Bredenoord A J . Predictive value of routine esophageal high-resolution manometry for gastro-esophageal reflux disease . Neurogastroenterol Motil 2015 ; 27 : 963 – 70 . Google Scholar CrossRef Search ADS PubMed 18 Weijenborg P W , van Hoeij F B , Smout A J , Bredenoord A J . Accuracy of hiatal hernia detection with esophageal high-resolution manometry . Neurogastroenterol Motil 2015 ; 27 : 293 – 9 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

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Diseases of the EsophagusOxford University Press

Published: Mar 31, 2018

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